Chiral specific boron-containing compounds and their use in treating cancer or amyloidosis

ABSTRACT

Useful chiral specific boron-containing compounds, such as boronate, boronate esters, boranamines, borane diamines, boranamine thioesters, and boronic mono/di-thioesters, have been prepared. These compounds and compositions containing them are useful as anti-cancer or anti-amyloidosis agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.15/186,988, filed Jun. 20, 2016 and now U.S. Pat. No. 10,144,761, whichclaims the benefit of U.S. Provisional Application Ser. No. 62/181,910,filed Jun. 19, 2015. The entire contents of each of the aforementionedapplications are incorporated herein by reference.

FIELD OF THE INVENTION

The invention herein is directed to chiral specific boron-containingcompounds, such as boronate, boronate esters, boranamines,boranediamines, boranamine thioesters, and boronic mono/di-thioesters,as anti-cancer or anti-amyloidosis agents, as well as theircompositions, methods of preparation, and methods of treatment.

BACKGROUND OF THE INVENTION

It is known that some peptide boronic acid compounds are proteasomeinhibitors, and they represent an important strategy in cancer therapy.Besides the marketed drug VELCADE® (Bortezomib or chemical name as[(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid) for the treatment of multiplemyeloma, other types of cancers, and amyloidosis. There are a number ofstructurally different peptide boronic acids at various stages ofclinical trials. One major issue of this group of boronic acids as(active pharmaceutical ingredient (API) is that they are not very stableat ambient conditions. The drug VELCADE®, for example, needs to bestored at below ambient temperature and kept away from light. Partiallyrelated to its instability, the drug VELCADE® is formulated as aninjection mixture, and patients must go to doctors' offices or hospitalsfor drug administration. Boronic acids are known to form many boronicacid derivatives, such as boronates and boronate esters. Boronates andboronate esters are able to be converted back to boronic acid undercertain conditions.

The present invention describes a group of boron-containing compounds,such as boronate, boronate esters, boranamines, boranediamines,boranamine thioesters, and boronic mono/di-thioesters, that are stableat ambient conditions. They can be formulated as both liquid and soliddrugs. Therefore, the bioactive component of the drug can be circulatedlonger in the human body and reach more areas unavailable to the directinjection into blood vessels.

DEFINITION OF TERMS

Unless otherwise explicitly stated, R is intended to refer an aliphaticor aromatic group.

Unless otherwise explicitly stated, the term “aliphatic” or “aliphaticgroup” is intended to refer a substituted or unsubstitutedstraight-chain, branched or cyclic C₁-C₁₂ hydrocarbon, which iscompletely saturated or which contains one or more units ofunsaturation, but which is not aromatic. Aliphatic group also includesatoms other than C in the backbone, such as, but not limited to, N, S,and O. Aliphatic group also includes one or more functional groupsattached to the backbone, such as, but not limited to, —OH, —SH, —CO—OH,—CO—OR (ester), —NH₂, —NHR—CO—R (ketone), —O—SO₂ (sulfonate), —NH—SO₂(sulfonamide) and —NR—SO₂ (sulfonamide).

Unless otherwise explicitly stated, the term “aromatic” or “aromaticgroup” is intended to refer a substituted or unsubstituted planarunsaturated ring of atoms that is stabilized by an interaction of thebonds forming the ring. Atoms forming an aromatic group include, but arenot limited to, C, O, S, and N.

Unless otherwise explicitly stated, the term “peptide” is intended torefer to a short chain of amino acid monomers linked by amide (—NH—CO—or —NR—CO—) bonds. R represents an aliphatic or aromatic group. Each Catom in the amino acid monomer may have one or two substitution groups,and the substitution groups are aliphatic, aromatic or both aliphaticand aromatic. The covalent chemical bonds are formed when the carboxylgroup of one amino acid reacts with the amino group of another.

Unless otherwise explicitly stated, the term “backbone” is intended torefer to the longest hydrocarbon chain in a molecule or a group. It alsorefers to the longest hydrocarbon chain with other atoms in the chain,such as, but not limited to, O, S, and N, in a molecule or a group.

Boronate, boronate esters, boranamines, boranediamines, boranaminethioesters and boronic mono/di-thioesters are illustrated by thecorresponding general structures showed below.

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Also, unlessotherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at anabundance that is at least 3000 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 45% incorporation ofdeuterium).

SUMMARY OF THE INVENTION

The present invention provides novel boron-containing compounds andstable pharmaceutically acceptable compositions comprising them. Thesecompounds are useful in treatment of diseases, such as cancers,cancerous conditions, plaque, or a plaque-forming condition such asamyloidosis, in a human or warm-blooded animal or mammal.

In one aspect of the invention, compounds of the general formula (I), orpharmaceutically acceptable salts thereof, are provided:

wherein:

Z₃ is a peptide containing 1-20 amide bonds and the boron atom informula (I) attaches to a C atom, not an N atom nor —C═O;

Z₁ and Z₂ are structurally the same or different side chains attached toboron atom in the formula (I);

Z₁ and Z₂ are each represented by the formula:

—X—R₁  Formula (II)

wherein:

X is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —SO₂, —NH—SO₂, or —NR—SO₂, Rbeing an aliphatic or aromatic substitution group; and

R₁ is an aliphatic chain with C₁-C₂₀ hydrocarbon; R₁ also represents analiphatic chain with C₁-C₂₀ hydrocarbon which has one or more X in thebackbone; R₁ also represents an aliphatic chain with C₁-C₂₀ hydrocarbonwhich has one or more aliphatic, aromatic, or both aliphatic andaromatic substitution groups on the backbone.

In another aspect of the invention, compounds of the general formula(III), or pharmaceutically acceptable salts thereof, are provided:

wherein:

Z₃ is a peptide containing 1-20 amide bonds and the boron atom attachesin formula (III) to a C atom, not an N atom nor —C═O;

Z₄ and Z₅ each attach to the boron atom in the formula (III) and alsojoin together on the other end to form a ring;

the ring formed by joining Z₄ and Z₅ together with boron is representedby formula (IV):

the ring size counting all atoms on the backbone of the ring in formula(IV) is 4-20 atoms; and

the backbone of the compound in formula (IV) constructed with atoms suchas, but not limited to, B, C, O, S, and N:

wherein:

X₁ and X₂ in formula (IV) are atoms or links or linkers, and they arethe same or different;

X₁ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₂ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

R is an aliphatic or aromatic substitution group; and

R₂ in formula (IV) represents the rest of the backbone of the ringbesides B, X₁, and X₂: R₂ also represents an aliphatic chain with C₁-C₂₀hydrocarbon which has one or more X₁ or X₂ in the backbone; R₂ alsorepresents an aliphatic chain with C₁-C₂₀ hydrocarbon which has one ormore aliphatic, aromatic, or both aliphatic and aromatic substitutiongroups on the backbone.

In some cases, two substitutions on the backbone of R₂ also form anotherring A which is illustrated by formula (V):

wherein:

the size of ring A in formula (V) is 3-10 atoms; and

Ring A in formula (V) is constructed by atoms such as, but not limitedto, C, O, S, or N.

In another aspect of the invention, compounds of the general formula(VI), or pharmaceutically acceptable salts thereof, are provided:

wherein:

Z₃ is a peptide containing 1-20 amide bonds and each boron atom attachesto a C atom, not an N atom nor —C═O;

Rings B and C are the same or different;

Rings B and C have the same descriptions as compounds represented byformula (III);

X₃ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₄ is O, S, NH, NR, O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₅ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₆ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

R is an aliphatic or aromatic substitution group;

Rings B and C in compounds represented by formula (VI) are connected bylink or linker R₃;

In compounds represented by formula (VI), link or linker R₃ connectswith X₇ in ring B and X₈ in ring C;

In compounds represented by formula (VI), X₇ is C, N, or other atoms orgroups that can form three bonds; X₈ is C, N, or other atoms or groupthat can form three bonds; and

In compounds represented by formula (VI), R₃ represents an aliphaticchain with C₁-C₁₀ hydrocarbon; R₃ also represents an aliphatic chainwith C₁-C₁₀ hydrocarbon which has one or more other atoms such as, butnot limited to, O, S, or N in the backbone; R₃ also represents analiphatic chain with C₁-C₁₀ hydrocarbon which has one or more aliphatic,aromatic, or both aliphatic and aromatic substitution groups on thebackbone.

In another aspect of the invention, compounds of the general formula(VII), or pharmaceutically acceptable salts thereof, are provided:

wherein:

Z₃ is a peptide containing 1-20 amide bonds and boron atom attaches to aC atom, not N atom nor —C═O;

Ring D in formula (VII) has two boron atoms;

the size of ring D counting for all atoms in the backbone of the ring informula (VII) is 6-20 atoms;

X₉, X₁₀, X₁₁, and X₁₂ in formula (VII) are the same or different;

X₉ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₁₀ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₁₁ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₁₂ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

R is an aliphatic or aromatic substitution group;

R₄ and R₅ in formula (VII) are the same or different;

In compounds represented by formula (VII), R₄ represents an aliphaticchain with C₁-C₁₀ hydrocarbon; R₄ also represents an aliphatic chainwith C₁-C₁₀ hydrocarbon which has one or more other atoms such as, butnot limited to, O, S, or N in the backbone; R₄ also represents analiphatic chain with C₁-C₁₀ hydrocarbon which has one or more aliphatic,aromatic, or both aliphatic and aromatic substitution groups on thebackbone; and

In compounds represented by formula (VII), R₅ represents an aliphaticchain with C₁-C₁₀ hydrocarbon; R₅ also represents an aliphatic chainwith C₁-C₁₀ hydrocarbon which has one or more other atoms such as, butnot limited to, O, S, or N in the backbone; R₅ also represents analiphatic chain with C₁-C₁₀ hydrocarbon which has one or more aliphatic,aromatic, or both aliphatic and aromatic substitution groups on thebackbone.

In another aspect of the invention, compounds of the general formula(VIII), or pharmaceutically acceptable salts or thereof, are provided:

wherein:

Z₃ is a peptide containing 1-20 amide bonds and each boron atom attachesto a C atom, not an N atom nor —C═O;

Ring E in formula (VIII) has three boron atoms;

the size of ring E counting for all atoms in the backbone of the ring informula (VII) is 9-20 atoms;

X₁₃, X₁₄, X₁₅, X₁₆, X₁₇, and X₁₈ in formula (VII) are the same ordifferent;

X₁₃ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO—O—SO₂, —NH—SO₂, or —NR—S₂;

X₁₄ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₁₅ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₁₆ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₁₇ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

X₁₈ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

R is an aliphatic or aromatic substitution group;

R₆, R₇, and R₈ in formula (VIII) are the same or different;

In compounds represented by formula (VIII), R₆ represents an aliphaticchain with C₁-C₁₀ hydrocarbon; R₆ also represents an aliphatic chainwith C₁-C₁₀ hydrocarbon which has one or more other atoms such as, butnot limited to, O, S, or N in the backbone; R₆ also represents analiphatic chain with C₁-C₁₀ hydrocarbon which has one or more aliphatic,aromatic, or both aliphatic and aromatic substitution groups on thebackbone;

In compounds represented by formula (VIII), R₇ represents an aliphaticchain with C₁-C₁₀ hydrocarbon; R₇ also represents an aliphatic chainwith C₁-C₁₀ hydrocarbon which has one or more other atoms such as, butnot limited to, O, S, or N in the backbone; R₇ also represents analiphatic chain with C₁-C₁₀ hydrocarbon which has one or more aliphatic,aromatic, or both aliphatic and aromatic substitution groups on thebackbone; and

In compounds represented by formula (VIII), R₈ represents an aliphaticchain with C₁-C₁₀ hydrocarbon; R₈ also represents an aliphatic chainwith C₁-C₁₀ hydrocarbon which has one or more other atoms such as, butnot limited to, O, S, or N in the backbone; R₈ also represents analiphatic chain with C₁-C₁₀ hydrocarbon which has one or more aliphatic,aromatic, or both aliphatic and aromatic substitution groups on thebackbone.

In another aspect of the invention, compounds of the general formula(IX), or pharmaceutically acceptable salts thereof, are provided:

wherein:

Z₃ is a peptide containing 1-20 amide bonds and the boron atom attachesto a C atom, not an N atom nor —C═O;

R₁₀ is a substitution branch on backbone of Z₃;

R₁₀ forms ring F with boron in formula (IX);

the size of ring F counting all atoms on the ring is 4-10 atoms;

X₁₉ is directly attached to boron in ring F;

X₁₉ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;R is an aliphatic or aromatic substitution group;

In compounds represented by formula (IX), R₁₀ represents an aliphaticchain with C₁-C₁₀ hydrocarbon; R₁₀ also represents an aliphatic chainwith C₁₋₁₀ hydrocarbon which has one or more other atoms such as, butnot limited to, O, S, or N in the backbone; R₁₀ also represents analiphatic chain with C₁-C₁₀ hydrocarbon which has one or more aliphatic,aromatic, or both aliphatic and aromatic substitution groups on thebackbone;

In compounds represented by formula (IX), X₂₀ is directly attached toboron and is not in ring F;

X₂₀ is O, S, NH, NR, —O—CO, —NH—CO, —NR—CO, —O—SO₂, —NH—SO₂, or —NR—SO₂;

R is an aliphatic or aromatic substitution group;

In compounds represented by formula (IX), R₉ attaches to X₂₀; and

R₉ represents an aliphatic chain with C₁₋₁₀ hydrocarbon; R₉ alsorepresents an aliphatic chain with C₁-C₁₀ hydrocarbon which has one ormore other atoms such as, but not limited to, O, S, or N in thebackbone; R₉ also represents an aliphatic chain with C₁-C₁₀ hydrocarbonwhich has one or more aliphatic, aromatic, or both aliphatic andaromatic substitution groups on the backbone.

In another aspect of the invention, a pharmaceutical compositioncomprises a compound of formula (I), (III), (IV), (V), (VI), (VII),(VIII), or (IX), or a pharmaceutically acceptable crystalline formthereof, suitable for the production of a drug in solid and/or liquidformulation.

Another aspect of the invention is directed to methods for the use of apharmaceutical composition comprising one or more of the compoundsdescribed above to treat a patient who has or is at risk to haveproteasome-mediated diseases, including cancers, or amyloidosis.

Non-toxic, pharmacologically acceptable salts useful herein compriseacid addition salts formed with inorganic or organic acids. Examples ofsuitable such salts include hydrohalides such as hydrochlorides,sulfates, hydrogen sulfates, phosphates, hydrogen phosphates, tartrates,succinates, maleates, benzoates, acetates, propionates, lactates,ascorbinates, and the like.

The compounds of formulae (I), (III), (IV), (V), (VI), (VII), (VIII),and (IX) according to the invention can be converted into theirnon-toxic, pharmacologically acceptable acid addition salts inconventional manner. Acids suitable for salt formation include, forexample, hydrochloric acid, hydrobromic acid, hydriodic acid,hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, aceticacid, propionic acid, butyric acid, caproic acid, valeric acid, oxalicacid, malonic acid, succinic acid, maleic acid, fumaric acid, lacticacid, tartaric acid, citric acid, malic acid, benzoic acid,p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamicacid, salicyclic acid, ascorbic acid, methanesulfonic acid,8-chlorotheophyllin, and the like.

The compounds of formulae (I), (III), (IV), (V), (VI), (VII), (VIII),and (IX) and pharmaceutically acceptable salts thereof can beincorporated, optionally in combination with other active ingredients,into the usual pharmaceutical preparations such as tablets, coatedtablets, capsules, powders, suppositories, or solutions. Suchpreparations may be produced with use of conventional pharmaceuticalexcipients, carriers, disintegrants, or lubricants or substances forobtaining delayed or sustained release. The single dose for adults isfrom about 0.1 to 80 mg (from about 0.0013 to 1.07 mg/kg), preferably,however, from about 1 to 30 mg (from about 0.013 to 0.40 mg/kg), 1 to 4times daily.

Dependent upon the type and body weight of the patient to be treated, onthe type and severity of the disease, on the type of preparation, and onthe route of administration, which may be peroral, parenteral, orrectal, as well as on the period or interval over which theadministration takes place, it may, however, be necessary to deviatefrom the above dosages. Thus, it may be sufficient in some cases toadminister less than the above-mentioned amount of active ingredient orin some cases the amount may be exceeded. The optimum dosage and routeof administration of the active ingredients which are necessary in eachcase can easily be determined by one skilled in the art.

Another aspect of the invention is directed to a compound of theformula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous forms, thereof,wherein:

Z₃ is a peptide containing 1-20 amide bonds and boron atom attaches to aC atom, not an N atom nor —C═O;

Y₃ is C₁ to C₅, O, S, NH, or NR;

R represents an aliphatic or aromatic group with or without heteroatomor functional group, such as COOH, OH, or NH₂;

each Ra₁ and Ra₂ independently is H, aliphatic, or aromatic substitutiongroup;

each Ra₃ and Ra₄ independently is H, aliphatic, or aromatic substitutiongroup;

q is 0, 1, or 2; and

r is 0, 1, or 2.

In another aspect of the invention, Z₃ is characterized by the barebones structure or its derivatives of formula (XI-1):

In another aspect of the invention, Z₃ is characterized by the barebones structure or its derivatives of formula (XI-2):

In another aspect of the invention, Z₃ is characterized by the barebones structure or its derivatives of formula (XI-3):

In another aspect of the invention, the compound is one of:

Another aspect of the invention is directed to a compound of theformula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof,wherein:

Z₃ is a peptide containing 1-20 amide bonds and boron atom attaches to aC atom, not an N atom or —C═O;

each of Y₁, Y₂, and Y₃ independently is O, S, NH, or NR; Y₃ can also beC₁ to C₅;

R represents an aliphatic or aromatic group with or without heteroatomor functional group, such as COOH, OH, or NH₂;

each Rb₁ and Rb₂ independently is H, aliphatic, or aromatic substitutiongroup; Rb₁ and Rb₂ can also be a double bond, such as carbonyl group;each Rb₃ and Rb₄ independently is H, aliphatic, or aromatic substitutiongroup;

s is 0, 1, or 2; and

t is 0, 1, or 2.

Another aspect of the invention is directed to the compoundcharacterized by the formula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof,wherein:

Z₃ is a peptide containing 1-20 amide bonds and boron atom attaches to aC atom, not an N atom nor —C═O;

each Rc₁ and Rc₂ independently is H, aliphatic, or aromatic substitutiongroup;

each Rc₃ and Rc₄ independently is H, aliphatic, or aromatic substitutiongroup, —(CH2)_(p)—COOH and —(CH2)_(p)—COOR wherein R is an aliphatic oraromatic group, with or without heteroatom or functional group, such asCOOH, OH, or NH₂; and

u is 0, 1, or 2.

In another aspect of the invention, the compound is characterized by theformula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous forms, thereof, wherein:

Z₃ is a peptide containing 1-20 amide bonds and boron atom attaches to aC atom, not an N atom nor —C═O; and

each Rd₁ and Rd₂ independently is H, aliphatic, aromatic substitutiongroup, —(CH2)_(p)—COOH and —(CH2)_(p)—COOR wherein R is an aliphatic oraromatic group with or without heteroatom or functional group, such asCOOH, OH, or NH₂.

In another aspect of the invention, the compound is characterized by theformula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof,wherein:

Z₃ is a peptide containing 1-20 amide bonds and boron atom attaches to aC atom, not an N atom nor —C═O;

each Re₁ and Re₂ independently is H, aliphatic, aromatic substitutiongroup, —(CH2)_(p)—COOH and —(CH2)_(p)—COOR wherein R is an aliphatic oraromatic group with or without heteroatom or functional group, such asCOOH, OH, or NH₂; and

each Re₃ and Re₄ independently is H, aliphatic, aromatic substitutiongroup, —(CH2)_(p)—COOH and —(CH2)_(p)—COOR wherein R is an aliphatic oraromatic group.

In another aspect of the invention, the compound is characterized by theformula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof,wherein:

Z₃ is a peptide containing 1-20 amide bonds and boron atom attaches to aC atom, not an N atom nor —C═O;

each Rf₁ and Rf₂ independently is H, aliphatic, aromatic substitutiongroup;

each Rf₃ and Rf₄ independently is H, aliphatic, aromatic substitutiongroup, —(CH₂)_(p)—COOH and —(CH₂)_(p)—COOR wherein R is an aliphatic oraromatic group with or without heteroatom or functional group, such asCOOH, OH, or NH₂; and

v is 0, 1, or 2.

In another aspect of the invention, the compound is characterized by theformula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof,wherein:

Z₃ is a peptide containing 1-20 amide bonds and boron atom attaches to aC atom, not an N atom nor —C═O;

R represents an aliphatic or aromatic group with or without heteroatomor functional group, such as COOH, OH, or NH₂;

each Rg₁ and Rg₂ independently is H, aliphatic, aromatic substitutiongroup;

each Rg₃ and Rg₄ independently is H, aliphatic, aromatic substitutiongroup, —(CH2)_(p)—COOH and —(CH2)_(p)—COOR wherein R is an aliphatic oraromatic group with or without heteroatom or functional group, such asCOOH, OH, NH₂; and

w is 0, 1, or 2.

In another aspect of the invention, the compound is one of thefollowing:

In another aspect of the invention, a medically useful compositioncomprises one or more of the compounds described herein in combinationwith pharmaceutically acceptable excipients, formulates as drugs insolid or liquid forms.

In another aspect of the medically useful compositions of the invention,the one or more compounds are present in an amount effective to treatcancer, a cancerous condition, such as multiple myeloma, or amyloidosisin a human or mammal.

Another aspect of the invention is directed a process for thepreparation of compounds of the formula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof,wherein:

Z₃ is a peptide containing 1-20 amide bonds and boron atom attaches to aC atom, not an N atom nor —C═O;

Y₃ is C₁ to C₅, O, S, NH, or NR; R represents an aliphatic or aromaticgroup with or without heteroatom or functional group, such as COOH, OH,or NH₂;

each Ra₁ and Ra₂ independently is H, aliphatic, aromatic substitutiongroup;

each Ra₃ and Ra₄ independently is H, aliphatic, aromatic substitutiongroup;

q is 0, 1, or 2; and

r is 0, 1, or 2.

In another aspect of the invention, a compound of formula (XI-1) isreacted with N-methyliminodiacetic acid to form a compound of formula(X-2):

wherein, HL01-0 is XI-1 and HL01-011 is X-2.

In another aspect of the invention, a compound of formula (XI-3) isreacted with N-methyliminodiacetic acid to form a compound of formula(X-2):

wherein, HL01-00 is XI-3 and HL01-015 is X-2.

In another aspect of the invention, a compound of formula (XI-2) isreacted with N-methyliminodiacetic acid to form a compound of formula(X-2):

wherein, HL01-000 is XI-2 and HL01-016 is X-2.

In another aspect of the invention, a compound of formula (XI-1) isreacted with EDTA to form a compound of formula (X-2):

wherein, HL01-0 is XI-1 and HL01-08 is X-2.

In another aspect of the invention, a compound of formula (XI-1) isreacted with EDTA to form a compound of formula (X-2):

wherein, HL01-0 is XI-1 and HL01-08-1 is X-2.

In another aspect of the invention, a compound of formula (XI-1) isreacted with N-ethyl-iminodiacetic acid to form a compound of formula(X-2):

wherein, HL01-0 is XI-1 and HL01-34 is X-2.

In another aspect of the invention, a compound of formula (XI-1) isreacted with N-methyldiethanolamine to form a compound of formula (XII):

wherein, HL01-0 is XI-1 and HL01-33 is XII.

In another aspect of the invention, a compound of formula (XI-3) iscoupled or reacted with an ester of amino substituted L-tartaric acidderivative to form a compound of formula (XI):

wherein, HL01-00 is XI-3 and HL-245 is XI.

In another aspect of the invention, a compound of formula (XI-1) isreacted with N-methyliminodiacetic acid to form a compound of formula(XII):

wherein, HL01-0 is XI-1 and HL-448 is XII.

In another aspect of the invention, a compound of formula (XI-1) iscoupled or reacted with N-ethyldiethanolamine to form a compound offormula (XII):

wherein, HL01-0 is XI-1 and HL-505 is XII.

In another aspect of the invention, a composition for treating cancer, acancerous condition, or amyloidosis in a human or mammal, comprises asactive ingredient a pharmaceutically effective amount of a compounddescribed herein, including, but not limited to, a compound of formulae(I), (III), (IV), (V), (VI), (VII), (VIII), and (IX) or apharmaceutically acceptable acid addition salt thereof, in combinationwith pharmaceutically acceptable carriers, diluents, or excipients.

In another aspect of the invention, the composition comprises activeingredient in an amount effective to treat multiple myeloma oramyloidosis.

In another aspect of the invention, in a method of treating cancer, acancerous condition, or amyloidosis in a human or mammal host in need ofsuch treatment, the method comprises perorally, parentally, or rectallyadministering to said host an effective cancer, cancerous condition, oramyloidosis treatment amount of a compound of formula (I), (III), (IV),(V), (VI), (VII), (VIII), or (IX) or a pharmaceutically acceptable acidaddition salt thereof.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE is a graph that represents the results of testing todemonstrate the cytotoxic effects of certain compounds, includingcompounds prepared according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention can perhaps be appreciated better from the descriptionbelow, where compounds of the invention have been prepared and then sometesting is described.

EXAMPLES

Boronic acid can readily form oligomeric anhydrides by dehydration ofthe boronic acid moiety. Hence, the monomeric structure form drawnbelow, such as HL01-0 drawn in the Example 1, is expressly intended torepresent the free boronic acid, oligomeric anhydrides, including, butnot limited to, dimers, trimers, and tetramers, and mixtures thereof.

Abbreviations: Bortezomib (HL01-0), Tetrahydrofuran (THF), Ethyl Acetate(EtOAc or EA), N,N-Dimethylsulfoxide (DMSO), EthylenediaminetetraaceticAcid (EDTA), Hydrogen Chloride (HCl), room temperature (RT), NuclearMagentci Resonance (NMR), Reverse Phase High Performance LiquidChromatography (RP-HPLC), Liquid Chromatography-Mass Spectroscopy(LC-MS)

General Characterization Methods: ¹H NMR, 13C NMR, HPLC, LCMS.

The product HL01-01 of Example 1, characterized by formula HL01-01-1,HL-01-01-2, HL-01-01-3, HL-01-01-4, HL-1-01-5, or a mixture thereof.

The product HL01-02 of Example 2, characterized by formula HL01-02-1,HL-01-02-2, HL-01-02-3, HL-01-02-4, or a mixture thereof.

The product HL01-17 of Example 15, characterized by formula HL01-17-1,HL-01-17-2, HL-01-17-3, HL-01-17-4, HL-1-17-5, or a mixture thereof.

The product HL01-18 of Example 16, characterized by formula HL01-18-1,HL-01-18-2, HL-01-18-3, HL-01-18-4, HL-1-18-5, or a mixture thereof.

The product HL01-23 of Example 23, characterized by formula HL01-23-1,HL-01-23-2, HL-01-23-3, HL-01-23-4, or a mixture thereof.

The product HL01-28 of Example 28, characterized by formula HL01-28-1,HL-01-28-2, HL-01-28-3, HL-01-28-4, or a mixture thereof.

Example 1

Bortezomib (HL01-0, 1.0 g) was dissolved in EA (80 mL) at 85° C., andcitric acid (525 mg, 2.73 mmol) was added under inert gas. The reactionmixture was stirred at 85° C. for another 3.5 hrs, then cooled to roomtemperature (RT), and n-Hexane (24 mL) was added. The white precipitatewas filtered and dried to get the white solid HL-01-01. ¹H NMR (d₆-DMSO,400 MHz) δ 12.08 (br, 1H), 10.62 (br, 1H), 9.19 (br, 1H), 9.18 (s, 1H),8.89 (s, 1H), 8.77 (s, 1H), 7.28-7.19 (m, 5H), 5.06 (m, 1H), 3.25 (d,2H, J=6.8 Hz), 2.85 (m, 1H), 2.72 (m, 2H), 2.57 (m, 2H), 1.45 (m, 1H),1.10 (m, 1H), 0.97 (m, 1H), 0.78 (d, 6H, J=4.4 Hz). 13C NMR (d₆-DMSO,400 MHz) δ 177.82, 170.73, 170.62, 163.28, 147.84, 143.98, 143.71,143.39, 129.28, 128.31, 126.79, 76.24, 50.31, 36.25, 24.55, 23.51,21.38.

Example 2

HL01-0 (100 mg) was dissolved in DMSO (2 mL), and L-malic acid (35 mg,0.26 mmol) was added under inert gas. The reaction mixture was stirredat 95° C. for 6 hrs, then cooled to RT. The solvent was removed underreduced pressure, then EA/n-Hexane was added to the residue at −20° C.The white precipitate was filtered and dried to get the white solid,HL-01-02. ¹H NMR (d₆-DMSO, 400 MHz) δ 12.30 (br, 1H), 10.72 (s, 1H),9.33 (d, 1H, J=7.6 Hz), 9.13 (d, 1H, J=1.6 Hz), 8.89 (d, 1H, J=1.6 Hz),8.78 (m, 1H), 7.28-7.21 (m, 5H), 5.07 (dd, 1H, J=15.2, 7.6 Hz), 4.37(dd, 1H, J=7.2, 4.0 Hz), 3.46-3.42 (m, 1H), 3.29-3.20 (m, 2H), 2.63-2.28(m, 2H), 1.46 (m, 1H), 1.17 (m, 2H), 0.81 (d, 6H, J=6.4 Hz). MS (m/z):[M+Na] calculated for C₂₃H₂₇BN₄NaO₇, 505.28; found, 505.19.

Example 3

HL01-0 (200 mg) was dissolved in EA (8 mL) at 85° C., and diethanolamine(54.7 mg, 0.52 mmol) was added under inert gas. The reaction mixture wasstirred at 85° C. for 6 hrs. then was cooled to RT. The whiteprecipitate was collected and dried to get the white solid.(150 mg, 63.¹H NMR (d₆-DMSO, 400 MHz) δ 9.09 (s, 1H), 8.87 (d, 1H, J=2.4 Hz), 8.81(d, 1H, J=8.8 Hz), 8.75 (s, 1H), 7.28-7.20 (m, 5H), 7.16-7.14 (m, 1H),6.55 (br, 1H), 4.76 (td, 1H, J=9.2, 4.8 Hz), 3.69-3.61 (m, 2H),3.28-3.23 (m, 1H), 3.48-3.41 (m, 1H), 3.16-3.04 (m, 3H), 2.85-2.77 (m,1H), 2.74-2.67 (m, 2H), 1.63-1.53 (m, 1H), 1.37-1.30 (m, 1H), 1.22-1.16(m, 1H), 0.80 (dd, 6H, J=12.8, 6.8 Hz).

Example 4

HL01-0 (384 mg) was dissolved in DMSO (3 mL) and EA (3 mL), andIminodiacetic Acid (133 mg, 1 mmol) was added under inert gas. Thereaction mixture was stirred at 85° C. for 6 hrs, then was cooled to RT.The white precipitate was collected under reduced pressure, washed byEtOH, and dried to get the white solid. ¹H NMR (d₆-DMSO, 400 MHz) δ 9.09(d, 1H, J=1.2 Hz), 8.87 (d, 1H, J=2.4 Hz), 8.73-8.72 (m, 1H), 8.70 (d,1H, J=8.8 Hz), 8.16 (br, 1H), 7.76 (d, 1H, J=8 Hz), 7.26-7.13 (m, 5H),4.72 (td, 1H, J=8.8, 5.6 Hz), 4.06 (dd, 1H, J=17.2, 8.4 Hz), 3.92 (dd,1H, J=17.6, 8.4 Hz), 3.76 (dd, 1H, J=9.2, 3.2 Hz), 3.72 (dd, 1H, J=9.2,3.2 Hz), 3.14-3.01 (m, 3H), 1.59-1.45 (m, 2H), 1.08-1.01 (m, 1H), 0.82(dd, 6H, J=22.4, 6.8 Hz). MS (m/z): [M+H] calculated for C₂₃H₂₉BN₅O₆,482.32; found, 482.15.

Example 5

HL01-0 (19.2 mg) was dissolved in DMSO (1.5 mL), and EDTA (7.3 mg, 0.05mmol) was added under inert gas. The reaction mixture was stirred at100° C. for 3 hrs, then was cooled to RT. The white precipitate wascollected under reduced pressure, and dried get the white solid. MS(m/z): [M+H] calculated for C₂₉H₃₈BN₆O₁₀, 641.46; found, 641.30.

Example 6

HL01-0 (50 mg) was dissolved in DMSO (2 mL), and EDTA (19 mg, 0.065mmol) was added under inert gas. The reaction mixture was stirred at105° C. for 4 hrs., then was cooled to RT. The white precipitate wascollected under reduced pressure, purified by semi-prep RP-HPLC, anddried get the white solid. MS (m/z): [M+H] calculated forC₄₈H₅₈B₂N₁₀O₁₂, 989.67; found, 989.2.

Example 7

HL01-0 (200 mg) was dissolved in DMSO/EA (6 mL/6 mL), andN-methyliminodiacetic acid 133 mg, 0.52 mmol) as added under inert gas.The reaction mixture was stirred at 85° C. for 5 hrs, and then wascooled to RT. The white precipitate was collected under reducedpressure, and dried to get the white solid. 1H NMR (d₆-DMSO, 400 MHz) δ9.07 (d, 1H, J=1.2 Hz), 8.92 (d, 1H, J=4.4 Hz), 8.87 (d, 1H, J=2.4 Hz),8.74-8.73 (m, 1H), 7.30-7.23 (m, 5H), 7.20-7.15 (m, 1H), 4.70-4.64 (m,1H), 4.22 (d, 1H, J=17.2 Hz), 4.07 (d, 1H, J=16.8 Hz), 3.98 (d, 1H,J=16.8 Hz), 3.57-3.51 (m, 2H), 3.09 (s, 1H), 3.07 (d, 1H, J=2.0 Hz),2.82 (s, 3H), 1.59-1.53 (m, 1H), 1.43-1.36 (m, 1H), 1.22-1.16 (m, 1H),0.84 (dd, 6H, J=11.2, 6.4 Hz). MS (m/z): [M+H] calculated forC₂₄H₃₁BN₅O₆, 496.34; found, 496.20.

Example 8

HL01-0 (150 mg) was dissolved in DMSO (5 mL), and N-isopropyliminodiacetic acid (HL01-12-0, 69 mg, 0.39 mmol) as added under inertgas. The reaction mixture was stirred at 85° C. for 5 hrs, and then wascooled to RT. The solvent was removed under reduced pressure to getcolorless oil. ¹H NMR (d₆-DMSO, 400 MHz) δ 9.09 (d, 1H, J=1.6 Hz), 8.91(d, 1H, J=8.4 Hz), 8.86 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=9.6 Hz),7.30-7.16 (m, 5H), 4.68-4.62 (m, 1H), 4.28 (d, 1H, J=18.0 Hz), 3.89 (dd,2H, J=18.4, 5.2 Hz), 3.71-3.61 (m, 3H), 3.09 (s, 1H), 3.07 (d, 1H, J=2.8Hz), 1.61-1.55 (m, 1H), 1.49-1.42 (m, 1H), 1.16 (dd, 6H, J=6.0, 2.0 Hz),0.99 (d, 1H, J=6.8 Hz), 0.84 (dd, 6H, J=29.2, 6.8 Hz). MS (m/z): [M+H]calculated for C₂₆H₃₅BN₅O₆, 524.4; found, 524.30.

Example 9

HL01-0 (200 mg) was dissolved in DMSO (3 mL), and N-benzyl iminodiaceticacid (HL01-13-0, 122 mg, 0.547 mmol) as added under inert gas. Thereaction mixture was stirred at 85° C. for 2 hrs, then was cooled to RT.The solvent was removed under reduced pressure to get colorless oil. 1HNMR (d₆-DMSO, 400 MHz) δ 9.12 (d, 1H, J=1.6 Hz), 9.06 (d, 1H, J=8.0 Hz),8.87 (d, 1H, J=2.0 Hz), 8.75 (dd, 1H, J=2.4, 1.6 Hz), 7.63-7.61 (m, 1H),7.52-7.50 (m, 2H), 7.34-7.17 (m, 7H), 4.66-4.60 (m, 1H), 4.465 (d, 1H,J=13.2 Hz), 4.26 (d, 1H, J=13.2 Hz), 4.18 (d, 1H, J=17.2 Hz), 3.85-3.77(m, 2H), 3.68-3.63 (m, 1H), 3.15-3.00 (m, 3H), 1.66-1.60 (m, 1H),1.56-1.45 (m, 1H), 1.35-1.26 (m, 1H), 0.89 (dd, 6H, J=11.2, 6.8 Hz). MS(m/z): [M+H] calculated for C₃₀H₃₅BN₅O₆, 572.44; found, 572.30.

Example 10

HL01-0 (200 mg) was dissolved in EA (5 mL), and Pinacol (61.5 mg) wasadded under inert gas. The reaction mixture was stirred at 85° C. for 5hrs, and then was cooled to RT, and the solvent was removed underreduced pressure to get the oil. 1H NMR (d₆-DMSO, 400 MHz) δ 9.18 (d,1H, J=1.2 Hz), 8.99-8.98 (m, 1H), 8.94 (d, 1H, J=2.8 Hz), 8.84 (d, 1H,8.4 Hz), 8.91-8.80 (m, 1H), 7.33-7.23 (m, 5H), 4.96-4.91 (m, 1H),3.19-3.17 (m, 2H), 2.70-2.66 (m, 1H), 1.65-1.56 (m, 1H), 1.37-1.31 (m,1H), 1.27-1.23 (m, 1H), 1.18 (d, 12H, J=4.8 Hz), 0.88 (t, 6H, J=6.4 Hz).MS (m/z): [M+H] calculated for C₂₅H₃₆BN₄O₄, 467.28; found: 467.30.

Example 11

Chloroacetic acid (6 g, 0.0625 mol) was dissolved in water (20 mL) at 0°C., then neutralized with 5 N NaOH solution. Isopropylamine (1.85 g,0.031 mol) was added to the solution and stirred at 50° C. overnight.BaCl₂ 2H₂O (7.6 g, 0.031 mol) was dissolved in hot water (15 mL) and wasadded to the reaction mixture. The precipitate was filtered and dried at60° C. for 2 hours. The solid was dissolved in the boiling water, and 5NH₂SO₄ was added. After removal of the precipitate, the filtrate wasconcentrated to give brown solid, HL01-12-0 (300 mg, 5.5%)¹H NMR(d6-DMSO, 400 MHz) δ 3.27 (s, 4H), 3.12 (s, 1H), 1.02 (s, 6H).

Example 12

Chloroacetic acid (18.9 g, 0.2 mol) was dissolved in water (30 mL) at 0°C., then neutralized with 5 N NaOH solution. Benzylamine (10.7 g, 0.1mol) was added to the solution and stirred at 60° C. overnight. BaCl₂2H₂O (25.6 g, 0.105 mol) was dissolved in hot water (30 mL) and wasadded to the reaction mixture. The precipitate was filtered and dried at80° C. for 4 hours. The solid was dissolved in the boiling water, and 5NH₂SO₄ was added. After removal of the precipitate, the filtrate wasconcentrated to give white solid, HL01-13-0 (8.0 g, 36%). 1H NMR(d6-DMSO, 400 MHz) δ 7.33-7.24 (m, 5H), 3.82 (s, 2H), 3.38 (s, 4H).

Example 13

HL01-00 (30 mg, 0.083) was dissolved in DMSO (2 mL), and N-Methyliminodiacetic acid (12.2 mg, 0.083 mmol) was added under inert gas. Thereaction mixture was stirred at 85° C. for 2 hrs, then was cooled to RT.The solvent was removed under reduced pressure and the residue purifiedby Prep-HPLC to get the white solid, HL01-15 (15 mg, 38.5%)¹H NMR(d6-DMSO, 400 MHz) δ 8.84 (s, 1H), 7.54-7.52 (m, 3H), 7.33 (d, 1H, J=8.8Hz), 4.26-4.13 (m, 3H), 4.02-3.80 (m, 4H), 2.87 (s, 3H), 1.53-1.52 (m,1H), 1.41-1.35 (m, 1H), 1.20-1.16 (m, 1H), 0.85 (m, 6H). MS (m/z): [M+H]calculated for C₁₉H₂₅BCl₂N₃O₆, 472.12; found, 472.00.

Example 14

HL01-000 (30 mg) was dissolved in DMSO (2 mL), and N-Methyliminodiacetic acid (10.7 mg, 0.073 mmol) was added under inert gas. Thereaction mixture was stirred at 85° C. for 2 hrs, then was cooled to RT.The solvent was removed under reduced pressure and the residue waspurified by Prep-HPLC to get the white solid, HL01-17 (10 mg, 36.3%). 1HNMR (d₆-DMSO, 400 MHz) δ 8.80 (d, 1H, J=8.4 Hz), 8.21-8.17 (m, 3H), 8.11(t, 1H, J=8.0 Hz), 8.00 (d, 1H, J=6.8 Hz), 7.59-7.25 (m, 4H), 5.21-5.20(m, 1H), 4.51 (dd, 1H, J=8.4, 3.6 Hz), 4.28 (d, 1H, J=17.6 Hz), 4.12 (d,1H, J=16.8 Hz), 4.08 (br, 1H), 3.97 (d, 1H, J=17.2 Hz), 3.92 (d, 1H,J=16.4 Hz), 2.94 (s, 3H), 1.55-1.48 (m, 1H), 1.45-1.37 (m, 1H),1.22-1.15 (m, 1H), 1.09 (d, 3H, J=6.0 Hz), 0.82 (dd, 6H, J=16.8, 6.8Hz). MS (m/z): [M+H] calculated for C₂₆H₃₄BN₄O₇, 525.25; found, 525.30.

Example 15

To a solution of HL01-00 (30 mg) in EA (2 mL) was added citric acid (16mg, 0.083 mmol) at sealed tube. The reaction mixture was stirred at 85°C. for 1.5 hrs. The reaction mixture was cooled to RT, and the solid wasfiltered to get the product white solid, HL01-17. (˜15 mg, 35.7%)¹H NMR(d₆-DMSO, 400 MHz) δ 12.18 (br, 1H), 10.72 (s, 1H), 9.13 (s, 1H), 7.66(s, 1H), 7.57 (d, 2H, J=1.2 Hz), 4.27 (br, 2H), 2.92-2.88 (m, 1H),2.78-2.74 (m, 1H), 2.67-2.63 (m, 1H), 2.53 (s, 1H), 1.68-1.67 (m, 1H),1.29-1.77 (m, 3H), 0.87 (d, 6H, J=6.4 Hz).

Example 16

HL01-000 (30 mg) was dissolved in DMSO (2 mL) at RT, and then citrate(14 mg, 0.073 mmol) was added. The reaction mixture was stirred at 85°C. under inert gas for another 4 hrs, then cooled to RT, The solvent wasremoved to get solid (15 mg). 1H NMR (d₆-DMSO, 400 MHz) δ 12.14 (s, 1H),10.78 (s, 1H), 8.81-8.79 (d, 1H, J=8.4 Hz), 8.24-8.19 (m, 3H), 8.15-8.11(t, 1H), 8.04-8.03 (d, 1H, J=7.2 Hz), 7.58-7.49 (m, 3H), 5.7 (s, 1H),4.72-4.69 (dd, 1H), 4.27 (s, 1H), 2.90-2.67 (m, 4H), 1.62 (s, 1H),1.30-1.14 (d, 5H), 0.83-0.82 (d, 6H, J=6.4 Hz).

Example 17

HL01-000 (30 mg) was dissolved in DMSO (2 mL) at RT, and theniminodiacetic acid (9.71 mg, 0.073 mmol) was added. The reaction mixturewas stirred at 85° C. under inert gas for another 5 hrs, then cooled toRT. The solvent was removed to get white crystalline solid, HL01-19(15mg). ¹H NMR (d₆-DMSO, 400 MHz) δ 8.78-8.76 (d, 1H, J=8.0 Hz), 8.21-8.16(m, 3H), 8.12-8.08 (t, 2H), 8.02-8.00 (d, 1H), 7.74-7.73 (d, 1H, J=7.6Hz), 7.58-7.49 (m, 3H), 5.16 (s, 1H), 4.41-4.38 (q, 1H), 4.15-4.07 (m,3H), 3.79-3.72 (m, 2H), 3.19-3.13 (m, 1H), 1.65-1.62 (m, 1H), 1.56-1.48(m, 1H), 1.11-1.04 (m, 3H), 0.86-0.85 (d, 3H=6.8 Hz), 0.80-0.78 (d, 3H,J=6.4 Hz). MS (m/z): [M+H] calculated for C₂₅H₃₂BN₄O₇, 511.35; found,511.0.

Example 18

HL01-000 (30 mg) was dissolved in DMSO (2 mL) at RT, and Pinacol (8.61mg, 0.073 mmol) was added. The reaction mixture was stirred at 85° C.under inert gas for another 5 hrs, then cooled to RT. The solvent wasremoved to get solid, HL01-20 (10 mg). 1H NMR (d₆-DMSO, 400 MHz) δ 9.11(s, 1H), 8.78-8.76 (d, 1H, J=8.4 Hz), 8.23-8.19 (m, 3H), 8.13-8.10 (t,1H), 8.03-8.01 (d, 1H, J=7.2 Hz), 7.57-7.50 (m, 4H), 5.32-5.31 (d, 1H,J=4.8 Hz), 4.55-4.51 (dd, 1H), 4.15-4.11 (dd, 1H), 1.68-1.64 (m, 1H),1.29-1.20 (m, 2H), 1.14-1.09 (m, 12H), 0.85-0.83 (dd, 6H)

Example 19

HL01-000 (30 mg) was dissolved in DMSO (2 mL) at RT, and N-isopropyliminodiacetic (8.61 mg, 0.073 mmol) was added. The reaction mixture wasstirred at 85° C. under inert gas for another 5 hrs, and then cooled toRT. The solvent was removed to get pale yellow sticky solid, HL01-21. ¹HNMR (d₆-DMSO, 400 MHz) δ 8.76-8.74 (d, 1H, J=8.4 Hz), 8.18-8.16 (m, 3H),8.12-8.08 (t, 1H), 8.02-8.00 (d, 1H), 7.59-7.51 (m, 4H), 5.17 (s, 1H),4.56-4.53 (dd, 1H), 4.33-4.28 (d, 1H), 4.08 (s, 1H), 3.99-3.89 (d, 3H),3.83-3.80 (t, 1H), 3.71-3.67 (t, 1H), 1.59-1.37 (m, 3H), 1.23-1.10 (dd,6H), 0.860.79 (m, 6H) MS (m/z): [M+H] calculated for C₂₈H₃₈BN₄O₇,553.43; found, 553.3.

Example 20

HL01-000 (30 mg) was dissolved in DMSO (2 mL) at RT, and EDTA (10.65 mg,0.037 mmol) was added, the reaction mixture was stirred at 98° C. underinert gas for another 6 hrs, then cooled to RT. The solvent was removedto get solid which was purified by RP-HPLC to give HL01-220-1 and dimerHL01-22-2. HL01-22-1 MS (m/z): [M+H] calculated for C₃₁H₄₁BN₅O₁₁,670.28; found, 670.2. HL01-22-2 MS (m/z): [M+H] calculated forC₅₂H₆₅B₂N₈O₁₄, 1047.47; found, 1047.1.

Example 21

HL01-000 (30 mg) was dissolved in DMSO (2 mL) at RT, and L-malic acid(9.79 mg, 0.073 mmol) was added, the reaction mixture was stirred at 98°C. under inert gas for another 6 hrs, then cooled to RT. The solvent wasremoved to get solid. which NMR (d₆-DMSO, 400 MHz) δ 12.30 (s, 1H),10.87 (s, 1H), 8.83-8.81 (d, 1H, J=8 Hz), 8.24-8.02 (m, 5H), 7.59-7.52(for, 3H), 5.77-5.76 (d, 1H, J=5.2 Hz), 4.76-4.73 (HL-22-2, 1H),4.41-4.39 ([M+H], 1H), 4.32-4.29 (m, 1H), 2.68-2.57 (m, 2H), 1.63-1.56(m, 1H), 1.31-1.26 (t, 2H), 1.19-1.18 (d, 3H, J=6.4 Hz), 0.84-0.83 (d,6H, J=6.4 Hz)

Example 22

HL01-00 (30 mg) was dissolved in DMSO (2 mL) at RT, and IminodiaceticAcid (11.03 mg, 0.083 mmol) was added. The reaction mixture was stirredat 85° C. under inert gas for another 5 hrs, then cooled to RT. Thesolvent was removed to get solid. 1H NMR (d6-DMSO, 400 MHz) δ 8.75-8.72(t, 1H), 8.19 (s, 1H), 7.69-7.68 (m, 1H), 7.52-7.51 (d, 2H, J=1.2 Hz),4.15-4.0 (m, 2H), 3.88-3.72 (m, 4H), 3.14-3.08 (m, 1H), 1.65-1.62 (m,1H), 1.54-1.46 (m, 1H), 1.12-1.06 (m, 1H), 0.88-0.81 (dd, 6H, J=6.8,21.6 Hz). MS (m/z): [M+H] calculated for C18H22BCl2N3O6, 458.09; found,458.4.

Example 23

HL01-00 (30 mg) was dissolved in EA (2 mL) at RT, and pinacol (9.79 mg,0.083 mmol) was added. The reaction mixture was stirred at 98° C. underinert gas for another 6 hrs, then cooled to RT. The solvent was removedto get solid. 1H NMR (d₆-DMSO, 400 MHz) δ 9.07 (s, 1H), 8.88-8.85 (t,1H), 7.70 (s, 1H), 7.53 (s, 2H), 4.04-4.02 (d, 2H, J=6 Hz), 2.66-2.57(m, 1H), 1.71-1.67 (m, 2H), 1.52-1.47 (m, 1H), 1.08 (s, 12H), 0.87-0.84(t, 6H)

Example 24

HL01-00 (30 mg) was dissolved in DMSO (1 mL) at RT, and N-isopropyliminodiacetic acid (14.53 mg, 0.083 mmol) was added. The reactionmixture was stirred at 98° C. under inert gas for another 6 hrs, thencooled to RT. The solvent was removed to get solid. 1H NMR (d₆-DMSO, 400MHz) δ 8.78 (s, 1H), 7.68 (s, 1H), 7.49-7.47 (d, 3H, J=8 Hz), 4.32-4.28(d, 1H, J=16.8 Hz), 4.05-3.88 (m, 4H), 3.74-3.67 (m, 3H), 1.54 (s, 1H),1.44-1.38 (t, 2H), 1.23-1.06 (m, 7H), 0.86-0.82 (d, 6H, J=15.2 Hz). MS(m/z): [M+H] calculated for C₂₁H₂₉BCl₂N₃O₆, 501.18; found, 502.1.

Example 25

HL01-00 (30 mg) was dissolved in DMSO (1 mL) at RT, and EDTA (24.23 mg,0.083 mmol) was added. The reaction mixture was stirred at 98° C. underinert gas for another 6 hrs, then cooled to RT. The solvent was removedto get solid which was purified by RP-HPLC to obtain HL01-27-1 and dimerHL01-27-2. HL01-27-1 MS (m/z): [M+H] calculated for C₂₄H₃₂BCl₂N₄O₁₀,618.24; found, 618.4; HL01-27-2 MS (m/z): [M+H] calculated forC₃₈H₄₇B₂C₁₄N₆O₁₂, 943.24; found: 943.4.

Example 26

HL01-00 (30 mg) was dissolved in DMSO (1 mL) at RT, and L-malic acid(11.12 mg, 0.083 mmol) was added. The reaction mixture was stirred at98° C. under inert gas for another 6 hrs, then cooled to RT. The solventwas removed to get solid. ¹H NMR (d₄-CD₃OD, 400 MHz) δ 7.59-7.56 (t,2H), 7.46 (dd, 1H, J=2 Hz, 8.4 Hz), 4.591-4.565 (q, 1H), 4.37 (s, 2H),2.87-2.78 (m, 2H), 2.61-2.58 (m, 1H), 1.74-1.64 (m, 1H), 1.47-1.43 (t,2H), 0.96-0.94 (dd, 6H, J=2.8 Hz, 6.8 Hz)

Example 27

HL01-00 (30 mg) was dissolved in DMSO (1 mL) at RT, andNitrilotri-acetic acid (15.85 mg, 0.083 mmol) was added. The reactionmixture was stirred at 85° C. under inert gas for another 5 hrs, thencooled to RT. The solvent was removed to get solid. 1H NMR (d₆-DMSO, 400MHz) δ 8.81-8.78 (t, 1H), 7.69-7.68 (t, 1H), 7.50-7.38 (m, 3H),4.43-4.38 (d, 1H, J=20 Hz), 4.30-4.25 (d, 1H, J=16.8 Hz), 4.21-4.00 (m,4H), 3.91-3.86 (dd, 1H, J=5.2 Hz, 15.6 Hz), 3.68-3.63 (dd, 1H, J=6.4 Hz,16 Hz), 3.59-3.53 (m, 1H), 1.56-1.53 (m, 1H), 1.39-1.36 (m, 1H),1.21-1.17 (m, 1H), 0.85 (dd, 6H, J=6.4 Hz, 14 Hz). MS (m/z): [M+H]calculated for C₂₀H₂₅BCl₂N₃O₈, 517.14; found, 517.3.

Example 28

HL01-000 (30 mg) was dissolved in DMSO (1 mL) at RT, andNitrilotri-acetic acid (13.94 mg, 0.073 mmol) was added. The reactionmixture was stirred at 85° C. under inert gas for another 5 hrs, thencooled to RT. The solvent was removed to get solid. 1H NMR (d₆-DMSO, 400MHz) δ 8.83-8.78 (t, 1H), 8.22-8.18 (t, 2H), 8.12-8.08 (t, 1H),8.03-7.98 (t, 1H), 7.59-7.48 (m, 5H), 4.53-4.50 (m, 1H), 4.46-4.42 (d,1H, J=17.6 Hz), 4.35-4.02 (m, 4H), 3.61-3.55 (m, 1H), 3.50 (s, 2H),1.55-1.46 (m, 1H), 1.45-1.38 (m, 2H), 1.10-1.08 (d, 3H, J=6.4 Hz),0.85-0.79 (m, 6H). MS (m/z): [M+H] calculated for C₂₇H₃₄BN₄O₉, 569.38;found, 569.5.

Example 29

HL01-0 (30 mg) was dissolved in DMSO (1 mL) at RT, and Nitrilotriaceticacid (14.89 mg, 0.078 mmol) was added. The reaction mixture was stirredat 85° C. under inert gas for another 6 hrs, then cooled to RT. Thesolvent was removed to get solid. 1H NMR (d₆-DMSO, 400 MHz) δ 9.07-9.06(d, 1H, J=1.2 Hz), 8.92-8.83 (m, 2H), 8.74-8.70 (m, 1H), 7.40-7.38 (d,1H, J=10 Hz), 7.29-7.12 (m, 5H), 4.71-4.65 (m, 1H), 4.40-4.04 (m, 4H),3.55-3.55 (m, 3H), 3.09-3.06 (m, 2H), 1.60-1.51 (m, 1H), 1.45-1.38 (m,1H), 1.23-1.17 (m, 1H), 0.84 (dd, 6H, J=6.4 Hz, 18.4 Hz). MS (m/z):[M+H] calculated for C₂₅H₃₁BN₅O₈, 540.35; found, 540.3.

Example 30

HL01-0 (30 mg) was dissolved in DMSO (1 mL) at RT, and L(+)-tartaricacid (11.70 mg, 0.078 mmol) was added, The reaction mixture was stirredat 85° C. under inert gas for another 5 hrs, then cooled to RT, Thesolvent was removed to get solid. 1H NMR (d₆-DMSO, 400 MHz) δ12.75 (bs,1H), 10.77 (s, 1H), 9.38-9.35 (t, 1H), 9.12 (s, 1H), 8.90-8.89 (d, 1H,J=2.4 Hz), 8.78-8.77 (t, 1H), 7.29-7.18 (m, 5H), 5.12-5.07 (q, 1H),4.49-4.21 (q, 2H), 3.32-3.21 (m, 2H), 2.68-2.57 (m, 1H), 1.55-1.37 (m,1H), 1.23-1.06 (m, 2H), 0.86-0.79 (q, 6H).

Example 31

HL01-0 (60 mg) was dissolved in Ethyl acetate (1 mL) at RT, andN-methyldiethanolamine (18.56 mg, 0.156 mmol) was added. The reactionmixture was stirred at RT under inert gas for another 5 hrs, thensolvent was removed to get solid. 1H NMR (d₆-DMSO, 400 MHz) δ 9.24-9.22(d, 1H, J=8.4 Hz), 9.09-9.08 (d, 1H, J=1.2 Hz), 8.89-8.88 (d, 1H, J=2.4Hz), 8.79-8.78 (m, 1H), 7.30-7.12 (m, 5H), 6.74-6.72 (d, 1H, J=10 Hz),4.67-4.61 (m, 1H), 3.61-3.55 (m, 3H), 3.21-3.0 (m, 6H), 2.90-2.86 (m,1H), 1.55-1.49 (m, 1H), 1.23-1.15 (m, 2H), 0.84-0.78 (dd, 6H, J=6.4, 16Hz). 3H (N-Me) was contained in 2.5 (DMSO)

Example 32

HL01-0 (30 mg) was dissolved in DMSO (1 mL) at RT, andN-ethyl-iminodiacetic acid (12.57 mg, 0.078 mmol) was added. Thereaction mixture was stirred at 85° C. under inert gas for another 5hrs, then cooled to RT. The solvent was removed to get solid. 1H NMR(d₆-DMSO, 400 MHz) δ 9.12-9.08 (m 1H), 8.93-8.84 (m, 2H), 8.74-8.66 (m,1H), 7.35-7.12 (m, 5H), 4.93-4.87 (q, 1H), 4.81-4.75 (q, 1H), 4.71-4.65(q, 1H), 4.18-3.93 (m, 4H), 3.30-3.24 (q, 1H), 3.14-3.03 (m, 2H),1.56-1.49 (m, 1H), 1.41-1.25 (m, 2H), 1.22-1.13 (m, 3H), 0.86-0.74 (m,6H).

Example 33

HL01-00 (30 mg) was dissolved in ethyl acetate (1 mL) at RT, andN-methyldiethanolamine (9.87 mg, 0.083 mmol) was added, then thereaction mixture was stirred at RT under inert gas for another 5 hrs.The solvent was removed to get solid. 1H NMR (d₆-DMSO, 400 MHz) δ8.94-8.91 (t, 1H), 7.72 (s, 1H), 7.56-7.45 (m, 1H,), 6.51-6.48 (d, 1H,J=9.6 Hz), 3.77-3.62 (m, 6H), 3.20-3.11 (m, 3H), 2.94-2.91 (m, 1H),2.85-2.81 (m, 1H), 2.59 (s, 3H), 1.49 (s, 1H), 1.22-1.17 (m, 2H),0.84-0.79 (dd, 6H, J=6, 16.8 Hz). MS (m/z): [M+H] calculated forC₁₉H₂₉BCl₂N₃O₄, 445.16; found, 445.4.

Example 34

HL01-00 (30 mg, 0.078 mmol) was dissolved in DMSO (1 mL) at RT, andN-ethyl-iminodiacetic acid (12.57 mg, 0.078 mmol) was added. Thereaction mixture was stirred at 85° C. under inert gas for another 5hrs, then cooled to RT, The solvent was removed to get solid. 1H NMR(d₆-DMSO, 400 MHz) δ8.78-8.66 (dt, 1H), 7.69 (s, 1H), 7.52-7.44 (m, 2H),7.35-7.29 (m, 1H), 4.19-3.82 (m, 6H), 3.18-3.09 (m, 2H), 2.99 (s, 1H),1.61-1.43 (m, 1H), 1.38-1.28 (m, 2H), 1.20-1.11 (m, 3H), 0.87-0.82 (m,6H).

In addition to the foregoing, the above reaction schemes, and variationsthereof, can be used to prepare the compounds set forth in the followingtable:

TABLE 1 Serial # Structure Name HL-40

isopropyl (S)-2-((R)-3- methyl-1-((S)-3-phenyl- 2-(pyrazine-2-carboxamido)propan- amido)butyl)-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL-41

isopropyl 2-((S)-2-((R)- 3-methyl-1-((S)-3- phenyl-2-(pyrazine-2-carboxamido)propan- amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetateHL-42

tert-butyl (S)-2-((R)-3- methyl-1-((S)-3-phenyl- 2-(pyrazine-2-carboxamido)propan- amido)butyl)-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL-43

tert-butyl 2-((S)-2-((R)- 3-methyl-1-((S)-3- phenyl-2-(pyrazine-2-carboxamido)propan- amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetateHL-44

ethane-1,2-diyl (4S,4′S)-bis(2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate) HL-45

ethane-1,2-diyl bis(2- ((S)-2-((R)-3-methyl-1- ((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate) HL-46

ethane-1,2-diyl bis(2- ((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4- yl)acetate) HL-47

ethane-1,2-diyl bis(2- ((S)-2-((R)-1-((2S,3R)-3- hydroxy-2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate) HL-48

ethane-1,2-diyl(4S,4′S)- bis(2-((R)-1-((2S,3R)-3- hydroxy-2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate) HL-49

ethane-1,2-diyl (4S,4′S)-bis(2-((R)-1- (2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 6-oxo-1,3,2- dioxaborinane-4- carboxylate) HL-50

tert-butyl 2-((S)-2-((R)- 1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4- yl)acetate HL-51

(S)-tert-butyl 2-((R)-1- (2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 6-oxo-1,3,2- dioxaborinane-4- carboxylate HL-52

isopropyl (S)-2-((R)-1- (2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 6-oxo-1,3,2- dioxaborinane-4- carboxylate HL-53

isopropyl 2-((S)-2-((R)- 1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4- yl)acetate HL-54

(S)-methyl 2-((R)-1-(2- (2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 6-oxo-1,3,2- dioxaborinane-4- carboxylate HL-55

methyl 2-((S)-2-((R)-1- (2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4- yl)acetate HL-56

(S)-methyl 2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-6-oxo- 1,3,2-dioxaborinane-4- carboxylate HL-57

methyl 2-((S)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6-phenylpicolinamido)butan- amido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL-58

(S)-isopropyl 2-((R)-1- ((2S,3R)-3-hydroxy-2- (6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL-59

isopropyl 2-((S)-2-((R)- 1-((2S,3R)-3-hydroxy- 2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL-60

(S)-tert-butyl 2-((R)-1- ((2S,3R)-3-hydroxy-2- (6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL-61

tert-butyl 2-((S)-2-((R)- 1-((2S,3R)-3-hydroxy- 2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL-62

N-((S)-1-(((R)-3- methyl-1-((R)-4- (methylcarbamoyl)-6-oxo-1,3,2-dioxaborinan- 2-yl)butyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL-63

N-((S)-1-(((R)-3- methyl-1-((R)-4-(2- (methylamino)-2-oxoethyl)-5-oxo-1,3,2- dioxaborolan-2- yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL-64

N-((S)-1-(((R)-1-((R)-4- (isopropylcarbamoyl)- 6-oxo-1,3,2-dioxaborinan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL-65

N-((S)-1-(((R)-1-((R)-4- (2-(isopropylamino)-2- oxoethyl)-5-oxo-1,3,2-dioxaborolan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL-66

N-((S)-1-(((R)-1-((R)-4- (tert-butylcarbamoyl)-6-oxo-1,3,2-dioxaborinan- 2-yl)-3- methylbutyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL-67

N-((S)-1-(((R)-1-((R)-4- (2-(tert-butylamino)-2- oxoethyl)-5-oxo-1,3,2-dioxaborolan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL-68

N,N-ethane-1,2-diyl (4R,4′R)-bis(2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxamide) HL-69

N,N-ethane-1,2-diyl bis(2-((R)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetamide) HL-70

(R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-N-methyl-6-oxo-1,3,2- dioxaborinane-4- carboxamide HL-71

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((R)-4-(2- (methylamino)-2-oxoethyl)-5-oxo-1,3,2- dioxaborolan-2- yl)butyl)amino)-2-oxoethyl)benzamide HL-72

(R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-N-isopropyl-6-oxo- 1,3,2-dioxaborinane-4- carboxamide HL-73

2,5-dichloro-N-(2-(((R)- 1-((R)-4-(2- (isopropylamino)-2-oxoethyl)-5-oxo-1,3,2- dioxaborolan-2-yl)-3- methylbutyl)amino)-2-oxoethyl)benzamide HL-74

(R)-N-(tert-butyl)-2- ((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 6-oxo-1,3,2- dioxaborinane-4- carboxamide HL-75

N-(2-(((R)-1-((R)-4-(2- (tert-butylamino)-2- oxoethyl)-5-oxo-1,3,2-dioxaborolan-2-yl)-3- methylbutyl)amino)-2- oxoethyl)-2,5-dichlorobenzamide HL-76

(4R,4′R)-N,N′-(ethane- 1,2-diyl)bis(2-((R)-1-(2- (2,5-dichlorobenzamido)acet- amido)-3-methylbutyl)- 6-oxo-1,3,2-dioxaborinane-4- carboxamide) HL-77

N,N-ethane-1,2-diyl bis(2-((R)-2-((R)-1-(2- (2,5-dichlorobenzamido)acet- amido)-3-methylbutyl)- 5-oxo-1,3,2-dioxaborolan-4- yl)acetamide) HL-78

N,N-ethane-1,2- diyl(4R,4′R)-bis(2-((R)- 1-((2S,3R)-3-hydroxy- 2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxamide) HL-79

N,N-ethane-1,2-diyl (4R,4′R)-bis(2-((R)-1- ((2S,3R)-3-hydroxy-2- (6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxamide) HL-80

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((R)-4- (methylcarbamoyl)-6-oxo-1,3,2-dioxaborinan- 2-yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL-81

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((R)-4-(2- (methylamino)-2-oxoethyl)-5-oxo-1,3,2- dioxaborolan-2- yl)butyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL-82

N-((2S,3R)-3-hydroxy- 1-(((R)-1-((R)-4- (isopropylcarbamoyl)-6-oxo-1,3,2- dioxaborinan-2-yl)-3- methylbutyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL-83

N-((2S,3R)-3-hydroxy- 1-(((R)-1-((R)-4-(2- (isopropylamino)-2-oxoethyl)-5-oxo-1,3,2- dioxaborolan-2-yl)-3- methylbutyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL-84

N-((2S,3R)-1-(((R)-1- ((R)-4-(tert- butylcarbamoyl)-6-oxo-1,3,2-dioxaborinan-2- yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL-85

N-((2S,3R)-1-(((R)-1- ((R)-4-(2-(tert- butylamino)-2-oxoethyl)-5-oxo-1,3,2- dioxaborolan-2-yl)-3- methylbutyl)amino)-3-hydroxy-1-oxobutan-2- yl)-6- phenylpicolinamide HL-86

isopropyl (R)-2-((R)-3- methyl-1-((S)-3-phenyl- 2-(pyrazine-2-carboxamido)propan- amido)butyl)-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL-87

methyl (R)-2-((R)-3- methyl-1-((S)-3-phenyl- 2-(pyrazine-2-carboxamido)propan- amido)butyl)-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL-88

methyl 2-((R)-2-((R)-3- methyl-1-((S)-3-phenyl- 2-(pyrazine-2-carboxamido)propan- amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetateHL-89

isopropyl (R)-2-((R)-3- methyl-1-((S)-3-phenyl- 2-(pyrazine-2-carboxamido)propan- amido)butyl)-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL-90

isopropyl 2-((R)-2-((R)- 3-methyl-1-((S)-3- phenyl-2-(pyrazine-2-carboxamido)propan- amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetateHL-91

tert-butyl (R)-2-((R)-3- methyl-1-((S)-3-phenyl- 2-(pyrazine-2-carboxamido)propan- amido)butyl)-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL-92

tert-butyl 2-((R)-2-((R)- 3-methyl-1-((S)-3- phenyl-2-(pyrazine-2-carboxamido)propan- amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetateHL-93

ethane-1,2-diyl (4R,4′R)-bis(2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate) HL-94

ethane-1,2-diyl (4R,4′R)-bis(2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate) HL-95

2-((R)-4-(2-methoxy-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetic acid HL-96

2-((S)-4-(2-methoxy-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetic acid HL-97

(S)-4-(2-methoxy-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL-98

(R)-4-(2-methoxy-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL-99

2-((R)-4- (methoxycarbonyl)-2- ((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL- 100

2-((S)-4- (methoxycarbonyl)-2- ((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL 101

2-((R)-4-(2-methoxy-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetic acid HL- 102

2-((S)-4-(2-methoxy-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetic acid HL- 103

(S)-4-(2-methoxy-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 104

(R)-4-(2-methoxy-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 105

2-((S)-4- (methoxycarbonyl)-2- ((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL- 106

2-((R)-4- (methoxycarbonyl)-2- ((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL- 107

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-methoxy-2- oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acidHL- 108

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-methoxy-2- oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acidHL- 109

(S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-methoxy-2- oxoethyl)-6-oxo-1,3,2- dioxaborinane-4- carboxylic acidHL- 110

(R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-methoxy-2- oxoethyl)-6-oxo-1,3,2- dioxaborinane-4- carboxylic acidHL- 111

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(methoxycarbonyl)-6- oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 112

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(methoxycarbonyl)-6- oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 113

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-methoxy-2- oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acidHL- 114

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-methoxy-2- oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acidHL- 115

(S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-methoxy-2- oxoethyl)-6-oxo-1,3,2- dioxaborinane-4- carboxylic acidHL- 116

(R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-methoxy-2- oxoethyl)-6-oxo-1,3,2- dioxaborinane-4- carboxylic acidHL- 117

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(methoxycarbonyl)-6- oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 118

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(methoxycarbonyl)-6- oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 119

2-((R)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamide)butan-amido)-3- methylbutyl)-4-(2- methoxy-2-oxoethyl)-5-oxo-1,3,2-dioxaborolan- 4-yl)acetic acid HL- 120

2-((S)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- methoxy-2-oxoethyl)-5-oxo-1,3,2-dioxaborolan- 4-yl)acetic acid HL- 121

(S)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- methoxy-2-oxoethyl)-6- oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 122

(R)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- methoxy-2-oxoethyl)-6- oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 123

2-((R)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4- (methoxycarbonyl)-6- oxo-1,3,2-dioxaborinan-4-yl)acetic acid HL- 124

2-((S)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4- (methoxycarbonyl)-6- oxo-1,3,2-dioxaborinan-4-yl)acetic acid HL- 125

2-((R)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- methoxy-2-oxoethyl)-5-oxo-1,3,2-dioxaborolan- 4-yl)acetic acid HL- 126

2-((S)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- methoxy-2-oxoethyl)-5-oxo-1,3,2-dioxaborolan- 4-yl)acetic acid HL- 127

(S)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- methoxy-2-oxoethyl)-6- oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 128

(R)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-2- methoxy-2-oxoethyl)-6- oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 129

2-((S)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4- (methoxycarbonyl)-6- oxo-1,3,2-dioxaborinan-4-yl)acetic acid HL- 130

2-((R)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4- (methoxycarbonyl)-6- oxo-1,3,2-dioxaborinan-4-yl)acetic acid HL- 131

2-((S)-2-((R)-3-methyl- 1-((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-4-(2- (methylamino)-2-oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acid HL- 132

2-((R)-2-((R)-3-methyl- 1-((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-4-(2- (methylamino)-2-oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acid HL- 133

(R)-2-((R)-3-methyl-1- ((S)-3-phenyl-2- (pyrazine-2- carboxamido)propan-amido)butyl)-4-(2- (methylamino)-2- oxoethyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 134

(S)-2-((R)-3-methyl-1- ((S)-3-phenyl-2- (pyrazine-2- carboxamido)propan-amido)butyl)-4-(2- (methylamino)-2- oxoethyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 135

2-((R)-2-((R)-3-methyl- 1-((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-4- (methylcarbamoyl)-6-oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 136

2-((S)-2-((R)-3-methyl- 1-((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-4- (methylcarbamoyl)-6-oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 137

2-((S)-2-((R)-3-methyl- 1-((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-4-(2- (methylamino)-2-oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acid HL- 138

2-((R)-2-((R)-3-methyl- 1-((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-4-(2- (methylamino)-2-oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acid HL- 139

(R)-2-((R)-3-methyl-1- ((S)-3-phenyl-2- (pyrazine-2- carboxamido)propan-amido)butyl)-4-(2- (methylamino)-2- oxoethyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 140

(S)-2-((R)-3-methyl-1- ((S)-3-phenyl-2- (pyrazine-2- carboxamido)propan-amido)butyl)-4-(2- (methylamino)-2- oxoethyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 141

2-((S)-2-((R)-3-methyl- 1-((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-4- (methylcarbamoyl)-6-oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 142

2-((R)-2-((R)-3-methyl- 1-((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-4- (methylcarbamoyl)-6-oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 143

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(methylamino)-2- oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)aceticacid HL- 144

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(methylamino)-2- oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)aceticacid HL- 145

(R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(methylamino)-2- oxoethyl)-6-oxo-1,3,2- dioxaborinane-4- carboxylicacid HL- 146

(S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(methylamino)-2- oxoethyl)-6-oxo-1,3,2- dioxaborinane-4- carboxylicacid HL- 147

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(methylcarbamoyl)-6- oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 148

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(methylcarbamoyl)-6- oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 149

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(methylamino)-2- oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)aceticacid HL- 150

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(methylamino)-2- oxoethyl)-5-oxo-1,3,2- dioxaborolan-4- yl)aceticacid HL- 151

(R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(methylamino)-2- oxoethyl)-6-oxo-1,3,2- dioxaborinane-4- carboxylicacid HL- 152

(S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(methylamino)-2- oxoethyl)-6-oxo-1,3,2- dioxaborinane-4- carboxylicacid HL- 153

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(methylcarbamoyl)-6- oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 154

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(methylcarbamoyl)-6- oxo-1,3,2-dioxaborinan- 4-yl)acetic acid HL- 155

2-((S)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butanamido)-3- methylbutyl)-4-(2- (methylamino)-2- oxoethyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetic acid HL- 156

2-((R)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- (methylamino)-2- oxoethyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetic acid HL- 157

(R)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- (methylamino)-2- oxoethyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 158

(S)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- (methylamino)-2- oxoethyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 159

2-((R)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4- (methylcarbamoyl)-6- oxo-1,3,2-dioxaborinan-4-yl)acetic acid HL- 160

2-((S)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4- (methylcarbamoyl)-6- oxo-1,3,2-dioxaborinan-4-yl)acetic acid HL- 161

2-((S)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- (methylamino)-2- oxoethyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetic acid HL- 162

2-((R)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- (methylamino)-2- oxoethyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetic acid HL- 163

(R)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- (methylamino)-2- oxoethyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 164

(S)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4-(2- (methylamino)-2- oxoethyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 165

2-((S)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4- (methylcarbamoyl)-6- oxo-1,3,2-dioxaborinan-4-yl)acetic acid HL- 166

2-((R)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan-amido)-3- methylbutyl)-4- (methylcarbamoyl)-6- oxo-1,3,2-dioxaborinan-4-yl)acetic acid HL- 167

2-((S)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-3-methyl-1-((S)-3-phenyl- 2-(pyrazine-2- carboxamido)propan-amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acid HL- 168

2-((R)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-3-methyl-1-((S)-3-phenyl- 2-(pyrazine-2- carboxamido)propan-amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acid HL- 169

(R)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 170

(S)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 171

2-((R)-4- (dimethylcarbamoyl)-2- ((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL- 172

2-((S)-4- (dimethylcarbamoyl)-2- ((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL- 173

2-((S)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-3-methyl-1-((S)-3-phenyl- 2-(pyrazine-2- carboxamido)propan-amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acid HL- 174

2-((R)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-3-methyl-1-((S)-3-phenyl- 2-(pyrazine-2- carboxamido)propan-amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetic acid HL- 175

(R)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 176

(S)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 177

2-((S)-4- (dimethylcarbamoyl)-2- ((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL- 178

2,2′-(2-((R)-3-methyl-1- ((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-5-oxo-1,3,2- dioxaborolane-4,4-diyl)bis(N,N- dimethylacetamide) HL- 179

N-((S)-1-(((R)-1-((R)-4- (2-(dimethylamino)-2- oxoethyl)-4-(dimethylcarbamoyl)-6- oxo-1,3,2-dioxaborinan- 2-yl)-3-methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 180

N-((S)-1-(((R)-1-((S)-4- (2-(dimethylamino)-2- oxoethyl)-4-(dimethylcarbamoyl)-6- oxo-1,3,2-dioxaborinan- 2-yl)-3-methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 181

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(dimethylamino)- 2-oxoethyl)-5-oxo- 1,3,2-dioxaborolan-4- yl)aceticacid HL- 182

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(dimethylamino)- 2-oxoethyl)-5-oxo- 1,3,2-dioxaborolan-4- yl)aceticacid HL- 183

(R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(dimethylamino)- 2-oxoethyl)-6-oxo- 1,3,2-dioxaborinane-4-carboxylic acid HL- 184

(S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(dimethylamino)- 2-oxoethyl)-6-oxo- 1,3,2-dioxaborinane-4-carboxylic acid HL- 185

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(dimethylcarbamoyl)- 6-oxo-1,3,2- dioxaborinan-4- yl)acetic acid HL-186

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(dimethylcarbamoyl)- 6-oxo-1,3,2- dioxaborinan-4- yl)acetic acid HL-187

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(dimethylamino)- 2-oxoethyl)-5-oxo- 1,3,2-dioxaborolan-4- yl)aceticacid HL- 188

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(dimethylamino)- 2-oxoethyl)-5-oxo- 1,3,2-dioxaborolan-4- yl)aceticacid HL- 189

(R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(dimethylamino)- 2-oxoethyl)-6-oxo- 1,3,2-dioxaborinane-4-carboxylic acid HL- 190

(S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(dimethylamino)- 2-oxoethyl)-6-oxo- 1,3,2-dioxaborinane-4-carboxylic acid HL- 191

2-((S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(dimethylcarbamoyl)- 6-oxo-1,3,2- dioxaborinan-4- yl)acetic acid HL-192

2-((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(dimethylcarbamoyl)- 6-oxo-1,3,2- dioxaborinan-4- yl)acetic acid HL-193

(R)-2,2′-(2-(1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-5-oxo-1,3,2- dioxaborolane-4,4- diyl)bis(N,N- dimethylacetamide) HL- 194

(R)-2,2′-(2-(1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-5-oxo-1,3,2- dioxaborolane-4,4- diyl)bis(N,N- dimethylacetamide) HL- 195

(R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(dimethylamino)- 2-oxoethyl)-N,N- dimethyl-6-oxo-1,3,2-dioxaborinane-4- carboxamide HL- 196

(S)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet- amido)-3-methylbutyl)-4-(2-(dimethylamino)- 2-oxoethyl)-N,N- dimethyl-6-oxo-1,3,2-dioxaborinane-4- carboxamide HL- 197

2-((S)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-1-((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan- amido)-3-methylbutyl)-5-oxo- 1,3,2-dioxaborolan-4- yl)acetic acid HL- 198

2-((R)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-1-((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan- amido)-3-methylbutyl)-5-oxo- 1,3,2-dioxaborolan-4- yl)acetic acid HL- 199

(R)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-1- ((2S,3R)-3-hydroxy-2-(6- phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 200

(S)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-1- ((2S,3R)-3-hydroxy-2-(6- phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 201

2-((R)-4- (dimethylcarbamoyl)-2- ((R)-1-((2S,3R)-3- hydroxy-2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL- 202

2-((S)-4- (dimethylcarbamoyl)-2- ((R)-1-((2S,3R)-3- hydroxy-2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL- 203

2-((S)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-1-((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan- amido)-3-methylbutyl)-5-oxo- 1,3,2-dioxaborolan-4- yl)acetic acid HL- 204

2-((R)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-1-((2S,3R)-3-hydroxy-2- (6- phenylpicolinamido)butan- amido)-3-methylbutyl)-5-oxo- 1,3,2-dioxaborolan-4- yl)acetic acid HL- 205

(R)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-1- ((2S,3R)-3-hydroxy-2-(6- phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 206

(S)-4-(2- (dimethylamino)-2- oxoethyl)-2-((R)-1- ((2S,3R)-3-hydroxy-2-(6- phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylic acid HL- 207

2-((S)-4- (dimethylcarbamoyl)-2- ((R)-1-((2S,3R)-3- hydroxy-2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL- 208

2-((R)-4- (dimethylcarbamoyl)-2- ((R)-1-((2S,3R)-3- hydroxy-2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinan-4- yl)acetic acid HL- 209

2,2′-(2-((R)-1-((2S,3R)- 3-hydroxy-2-(6- phenylpicolinamido)butan-amido)-3- methylbutyl)-5-oxo- 1,3,2-dioxaborolane- 4,4-diyl)bis(N,N-dimethylacetamide) HL- 210

2,2′-(2-((R)-1-((2S,3R)- 3-hydroxy-2-(6- phenylpicolinamido)butan-amido)-3- methylbutyl)-5-oxo- 1,3,2-dioxaborolane- 4,4-diyl)bis(N,N-dimethylacetamide) HL- 211

N-((2S,3R)-1-(((R)-1- ((R)-4-(2- (dimethylamino)-2- oxoethyl)-4-(dimethylcarbamoyl)-6- oxo-1,3,2-dioxaborinan- 2-yl)-3-methylbutyl)amino)-3- hydroxy-1-oxobutan-2- yl)-6- phenylpicolinamideHL- 212

N-((2S,3R)-1-(((R)-1- ((S)-4-(2- (dimethylamino)-2- oxoethyl)-4-(dimethylcarbamoyl)-6- oxo-1,3,2-dioxaborinan- 2-yl)-3-methylbutyl)amino)-3- hydroxy-1-oxobutan-2- yl)-6- phenylpicolinamideHL- 213

methyl (4R,5R)-5- hydroxy-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 214

methyl (4R,5S)-5- hydroxy-2-((R)-3- methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 215

methyl (R)-2-hydroxy- 2-((R)-2-((R)-3-methyl- 1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL- 216

methyl (R)-2-hydroxy- 2-((R)-2-((R)-3-methyl- 1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL- 217

methyl (4R,5R)-2-((R)- 1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-hydroxy-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL- 218

methyl (4R,5S)-2-((R)- 1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-hydroxy-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL- 219

methyl (4R,5S)-2-((R)- 1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-hydroxy-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL- 220

methyl (R)-2-((R)-2- ((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4-yl)-2- hydroxyacetateHL- 222

methyl (4R,5R)-5- hydroxy-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 223

methyl (4R,5S)-5- hydroxy-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 224

methyl (R)-2-hydroxy- 2-((R)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6-phenylpicolinamido)butan- amido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL- 225

methyl (R)-2-hydroxy- 2-((R)-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6-phenylpicolinamido)butan- amido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL- 226

methyl (4R,5R)-5- amino-2-((R)-3-methyl- 1-((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL- 227

methyl (4R,5S)-5- amino-2-((R)-3-methyl- 1-((S)-3-phenyl-2- (pyrazine-2-carboxamido)propan- amido)butyl)-6-oxo-1,3,2- dioxaborinane-4-carboxylate HL- 228

methyl (R)-2-amino-2- ((R)-2-((R)-3-methyl-1- ((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL- 229

methyl (R)-2-amino-2- ((R)-2-((R)-3-methyl-1- ((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL- 230

methyl (4R,5R)-5- amino-2-((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 6-oxo-1,3,2- dioxaborinane-4- carboxylate HL- 231

methyl (4R,5S)-5- amino-2-((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 6-oxo-1,3,2- dioxaborinane-4- carboxylate HL- 232

methyl (R)-2-amino-2- ((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4- yl)acetate HL- 233

methyl (R)-2-amino-2- ((R)-2-((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4- yl)acetate HL- 234

methyl (4R,5R)-5- amino-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 235

methyl (4R,5S)-5- amino-2-((R)-1- ((2S,3R)-3-hydroxy-2- (6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 236

methyl (R)-2-amino-2- ((R)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL- 237

methyl (R)-2-amino-2- ((R)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL- 238

methyl (4R,5R)-2-((R)- 3-methyl-1-((S)-3- phenyl-2-(pyrazine-2-carboxamido)propan- amido)butyl)-5- (methylamino)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 239

methyl (4R,5S)-2- ((R)-3-methyl-1-((S)-3- phenyl-2-(pyrazine-2-carboxamido)propan- amido)butyl)-5- (methylamino)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 240

methyl (R)-2-((R)-2- ((R)-3-methyl-1-((S)-3- phenyl-2-(pyrazine-2-carboxamido)propan- amido)butyl)-5-oxo-1,3,2- dioxaborolan-4-yl)-2-(methylamino)acetate HL- 241

methyl (R)-2-((R)-2- ((R)-3-methyl-1-((S)-3- phenyl-2-(pyrazine-2-carboxamido)propan- amido)butyl)-5-oxo-1,3,2- dioxaborolan-4-yl)-2-(methylamino)acetate HL- 242

methyl (4R,5R)-2-((R)- 1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-(methylamino)-6-oxo- 1,3,2-dioxaborinane-4-carboxylate HL- 243

methyl (4R,5S)-2-((R)- 1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-(methylamino)-6-oxo- 1,3,2-dioxaborinane-4-carboxylate HL- 244

methyl (R)-2-((R)-2- ((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4-yl)-2-(methylamino)acetate HL- 245

methyl (R)-2-((R)-2- ((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4-yl)-2-(methylamino)acetate HL- 246

methyl (4R,5R)-2-((R)- 1-((2S,3R)-3-hydroxy- 2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-5- (methylamino)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 247

methyl (4R,5S)-2-((R)- 1-((2S,3R)-3-hydroxy- 2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-5- (methylamino)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 248

methyl (R)-2-((R)-2- ((R)-1-((2S,3R)-3- hydroxy-2-(6phenylpicolinamido)butan- amido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)-2- (methylamino)acetate HL- 249

methyl (R)-2-((R)-2- ((R)-1-((2S,3R)-3- hydroxy-2-(6-phenylpicolinamido)butan- anamido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)-2- (methylamino)acetate HL- 250

methyl (4R,5R)-5- (dimethylamino)-2- ((R)-1-((2S,3R)-3- hydroxy-2-(6-phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 251

methyl (4R,5S)-5- (dimethylamino)-2- ((R)-1-((2S,3R)-3- hydroxy-2-(6phenylpicolinamido)butan- amido)-3- methylbutyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 252

methyl (R)-2- (dimethylamino)-2- ((R)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6-phenylpicolinamido) butanamido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL- 253

methyl (R)-2- (dimethylamino)-2- ((R)-2-((R)-1-((2S,3R)- 3-hydroxy-2-(6-phenylpicolinamido) butanamido)-3- methylbutyl)-5-oxo-1,3,2-dioxaborolan-4- yl)acetate HL- 254

methyl (4R,5R)-2-((R)- 1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-(dimethylamino)-6- oxo-1,3,2- dioxaborinane-4-carboxylate HL- 255

methyl (4R,5S)-2-((R)- 1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-(dimethylamino)-6- oxo-1,3,2- dioxaborinane-4-carboxylate HL- 256

methyl (R)-2-((R)-2- ((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4-yl)-2-(dimethylamino)acetate HL- 257

methyl (R)-2-((R)-2- ((R)-1-(2-(2,5- dichlorobenzamido)acet-amido)-3-methylbutyl)- 5-oxo-1,3,2- dioxaborolan-4-yl)-2-(dimethylamino)acetate HL- 258

methyl (4R,5R)-5- (dimethylamino)-2- ((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 259

methyl (4R,5S)-5- (dimethylamino)-2- ((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2- carboxamido)propan- amido)butyl)-6-oxo-1,3,2-dioxaborinane-4- carboxylate HL- 260

methyl (R)-2- (dimethylamino)-2- ((R)-2-((R)-3-methyl-1-((S)-3-phenyl-2- (pyrazine-2- carboxamido)propan-amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetate HL- 261

methyl (R)-2- (dimethylamino)-2- ((R)-2-((R)-3-methyl-1-((S)-3-phenyl-2- (pyrazine-2- carboxamido)propan-amido)butyl)-5-oxo-1,3,2- dioxaborolan-4- yl)acetate HL- 262

N-((S)-1-(((R)-1-((R)- 5,6-dimethyl-4,8-dioxo- 1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2-carboxamide HL- 263

2,5-dichloro-N-(2-(((R)- 1-((R)-5,6-dimethyl- 4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-2- oxoethyl)benzamide HL- 264

N-((2S,3R)-1-(((R)-1- ((R)-5,6-dimethyl-4,8- dioxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 265

N-((S)-1-(((R)-1-((R)- 5,6-dimethyl-4,8-dioxo- 1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2-carboxamide HL- 266

2,5-dichloro-N-(2-(((R)- 1-((R)-5,6-dimethyl- 4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-2- oxoethyl)benzamide HL- 267

N-((2S,3R)-1-(((R)-1- ((R)-5,6-dimethyl-4,8- dioxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 268

N-((S)-1-(((R)-3- methyl-1-((5R,7R)- 5,6,7-trimethyl-4,8- dioxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 269

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((5R,7R)- 5,6,7-trimethyl-4,8-dioxo-1,3,6,2- dioxazaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamideHL- 270

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((5R,7R)-5,6,7-trimethyl-4,8-dioxo- 1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 271

N-((S)-1-(((R)-3- methyl-1-((5R,7S)- 5,6,7-trimethyl-4,8- dioxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 272

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((5R,7S)- 5,6,7-trimethyl-4,8-dioxo-1,3,6,2- dioxazaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamideHL- 273

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((5R,7S)-5,6,7-trimethyl-4,8-dioxo- 1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 274

N-((S)-1-(((R)-3- methyl-1-((5R,7R)- 5,6,7-trimethyl-4,8- dioxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 275

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((5R,7R)- 5,6,7-trimethyl-4,8-dioxo-1,3,6,2- dioxazaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamideHL- 276

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((5R,7R)-5,6,7-trimethyl-4,8-dioxo- 1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 277

N-((S)-1-(((R)-3- methyl-1-((5R,7S)- 5,6,7-trimethyl-4,8- dioxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 278

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((5R,7S)- 5,6,7-trimethyl-4,8-dioxo-1,3,6,2- dioxazaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamideHL- 279

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((5R,7S)-5,6,7-trimethyl-4,8-dioxo- 1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 280

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-11- methyl-2,6-dioxo-3,5-dioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 281

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 11-methyl-2,6-dioxo-3,5-dioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 282

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-11-methyl-2,6-dioxo-3,5-dioxa-11- aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6 phenylpicolinamide HL- 283

N-((S)-1-(((R)-3- methyl-1-((1R,7R)-11- methyl-2,6-dioxo-3,5-dioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 284

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7R)- 11-methyl-2,6-dioxo-3,5-dioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 285

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7R)-11-methyl-2,6-dioxo-3,5-dioxa-11- aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 286

N-((S)-1-(((R)-3- methyl-1-((1S,7S)-11- methyl-2,6-dioxo-3,5-dioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 287

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1S,7S)-11- methyl-2,6-dioxo-3,5-dioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 288

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1S,7S)-11-methyl-2,6-dioxo-3,5-dioxa-11-aza- 4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 289

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-11- methyl-2,6-dioxo-3,5-dioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 290

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 11-methyl-2,6-dioxo-3,5-dioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 291

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-11-methyl-2,6-dioxo-3,5-dioxa-11- aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 292

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-11- methyl-2,6-dioxo-3,5,9-trioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 293

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 11-methyl-2,6-dioxo-3,5,9-trioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 294

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-11-methyl-2,6-dioxo-3,5,9-trioxa- 11-aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 295

N-((S)-1-(((R)-3- methyl-1-((1R,7R)-11- methyl-2,6-dioxo-3,5,9-trioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 296

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7R)- 11-methyl-2,6-dioxo-3,5,9-trioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 297

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7R)-11-methyl-2,6-dioxo-3,5,9-trioxa- 11-aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 298

N-((S)-1-(((R)-3- methyl-1-((1S,7S)-11- methyl-2,6-dioxo-3,5,9-trioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 299

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1S,7S)-11- methyl-2,6-dioxo-3,5,9-trioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 300

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1S,7S)-11-methyl-2,6-dioxo-3,5,9-trioxa-11- aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 301

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-11- methyl-2,6-dioxo-3,5,9-trioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 302

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 11-methyl-2,6-dioxo-3,5,9-trioxa-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 303

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-11-methyl-2,6-dioxo-3,5,9-trioxa- 11-aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 304

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-11- methyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 305

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 11-methyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 306

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-11-methyl-2,6-dioxo-3,5-dioxa- 9,11-diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 307

N-((S)-1-(((R)-3- methyl-1-((1R,7R)-11- methyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 308

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7R)- 11-methyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 309

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7R)-11-methyl-2,6-dioxo-3,5-dioxa- 9,11-diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 310

N-((S)-1-(((R)-3- methyl-1-((1S,7S)-11- methyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 311

2,5-dichloro-N-(2- (((R)-3-methyl-1- ((1S,7S)-11-methyl-2,6-dioxo-3,5-dioxa-9,11- diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-2- oxoethyl)benzamide HL- 312

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1S,7S)-11-methyl-2,6-dioxo-3,5-dioxa-9,11- diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 313

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-11- methyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 314

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 11-methyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 315

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-11-methyl-2,6-dioxo-3,5-dioxa- 9,11-diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 316

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-11- methyl-2,6-dioxo-3,5-dioxa-9-thia-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 317

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 11-methyl-2,6-dioxo-3,5-dioxa-9-thia-11-aza- 4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-2- oxoethyl)benzamide HL- 318

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-11-methyl-2,6-dioxo-3,5-dioxa-9- thia-11-aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 319

N-((S)-1-(((R)-3- methyl-1-((1S,7S)-11- methyl-2,6-dioxo-3,5-dioxa-9-thia-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 320

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1S,7S)-11- methyl-2,6-dioxo-3,5-dioxa-9-thia-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 321

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1S,7S)-11-methyl-2,6-dioxo-3,5-dioxa-9-thia- 11-aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 322

N-((S)-1-(((R)-3- methyl-1-((1R,7R)-11- methyl-2,6-dioxo-3,5-dioxa-9-thia-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 323

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7R)- 11-methyl-2,6-dioxo-3,5-dioxa-9-thia-11-aza- 4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-2- oxoethyl)benzamide HL- 324

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7R)-11-methyl-2,6-dioxo-3,5-dioxa-9- thia-11-aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 325

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-11- methyl-2,6-dioxo-3,5-dioxa-9-thia-11-aza-4- borabicyclo[5.3.1]undecan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 326

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 11-methyl-2,6-dioxo-3,5-dioxa-9-thia-11-aza- 4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-2- oxoethyl)benzamide HL- 327

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-11-methyl-2,6-dioxo-3,5-dioxa-9- thia-11-aza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 328

N-((S)-1-(((R)-3- methyl-1-((1R,7R)-10- methyl-2,6-dioxo-3,5-dioxa-10-aza-4- borabicyclo[5.2.1]decan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 329

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7R)- 10-methyl-2,6-dioxo-3,5-dioxa-10-aza-4- borabicyclo[5.2.1]decan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 330

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7R)-10-methyl-2,6-dioxo-3,5-dioxa-10- aza-4- borabicyclo[5.2.1]decan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 331

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-10- methyl-2,6-dioxo-3,5-dioxa-10-aza-4- borabicyclo[5.2.1]decan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 332

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 10-methyl-2,6-dioxo-3,5-dioxa-10-aza-4- borabicyclo[5.2.1]decan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 333

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-10-methyl-2,6-dioxo-3,5-dioxa-10- aza-4- borabicyclo[5.2.1]decan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 334

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-10- methyl-2,6-dioxo-3,5-dioxa-10-aza-4- borabicyclo[5.2.1]decan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 335

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 10-methyl-2,6-dioxo-3,5-dioxa-10-aza-4- borabicyclo[5.2.1]decan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 336

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-10-methyl-2,6-dioxo-3,5-dioxa-10- aza-4- borabicyclo[5.2.1]decan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 337

N-((S)-1-(((R)-3- methyl-1-((1S,7S)-10- methyl-2,6-dioxo-3,5-dioxa-10-aza-4- borabicyclo[5.2.1]decan- 4-yl)butyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 338

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1S,7S)-10- methyl-2,6-dioxo-3,5-dioxa-10-aza-4- borabicyclo[5.2.1]decan- 4-yl)butyl)amino)-2-oxoethyl)benzamide HL- 339

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-10-methyl-2,6-dioxo-3,5-dioxa-10- aza-4- borabicyclo[5.2.1]decan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 340

N-((S)-1-(((R)-1- ((1R,7S)-9,11-dimethyl- 2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3- methylbutyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 341

2,5-dichloro-N-(2-(((R)- 1-((1R,7S)-9,11- dimethyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3-methylbutyl)amino)-2- oxoethyl)benzamide HL- 342

N-((2S,3R)-1-(((R)-1- ((1R,7S)-9,11-dimethyl- 2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3- methylbutyl)amino)-3-hydroxy-1-oxobutan-2- yl)-6- phenylpicolinamide HL- 343

N-((S)-1-(((R)-1- ((1R,7R)-9,11- dimethyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3-methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 344

2,5-dichloro-N-(2-(((R)- 1-((1R,7R)-9,11- dimethyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3-methylbutyl)amino)-2- oxoethyl)benzamide HL- 345

N-((2S,3R)-1-(((R)-1- ((1R,7R)-9,11- dimethyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3-methylbutyl)amino)-3- hydroxy-1-oxo-3- phenylpropan-2-yl)-6-phenylpicolinamide HL- 346

N-((S)-1-(((R)-1- ((1S,7S)-9,11-dimethyl- 2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3- methylbutyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 347

2,5-dichloro-N-(2-(((R)- 1-((1S,7S)-9,11- dimethyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3-methylbutyl)amino)-2- oxoethyl)benzamide HL- 348

N-((2S,3R)-1-(((R)-1- ((1S,7S)-9,11-dimethyl- 2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3- methylbutyl)amino)-3-hydroxy-1-oxobutan-2- yl)-6- phenylpicolinamide HL- 349

N-((S)-1-(((R)-1- ((1R,7S)-9,11-dimethyl- 2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3- methylbutyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 350

2,5-dichloro-N-(2-(((R)- 1-((1R,7S)-9,11- dimethyl-2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3-methylbutyl)amino)-2- oxoethyl)benzamide HL- 351

N-((2S,3R)-1-(((R)-1- ((1R,7S)-9,11-dimethyl- 2,6-dioxo-3,5-dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan- 4-yl)-3- methylbutyl)amino)-3-hydroxy-1-oxobutan-2- yl)-6- phenylpicolinamide HL- 352

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-11- methyl-2,6-dioxo-9-phenyl-3,5-dioxa-9,11- diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 353

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 11-methyl-2,6-dioxo-9-phenyl-3,5-dioxa-9,11- diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-2- oxoethyl)benzamide HL- 354

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-11-methyl-2,6-dioxo-9-phenyl-3,5- dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 355

N-((S)-1-(((R)-3- methyl-1-((1R,7R)-11- methyl-2,6-dioxo-9-phenyl-3,5-dioxa-9,11- diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 356

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7R)- 11-methyl-2,6-dioxo-9-phenyl-3,5-dioxa-9,11- diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-2- oxoethyl)benzamide HL- 357

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7R)-11-methyl-2,6-dioxo-9-phenyl-3,5- dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 358

N-((S)-1-(((R)-3- methyl-1-((1S,7S)-11- methyl-2,6-dioxo-9-phenyl-3,5-dioxa-9,11- diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 359

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1S,7S)-11- methyl-2,6-dioxo-9-phenyl-3,5-dioxa-9,11- diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-2- oxoethyl)benzamide HL- 360

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1S,7S)-11-methyl-2,6-dioxo-9-phenyl-3,5- dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 361

N-((S)-1-(((R)-3- methyl-1-((1R,7S)-11- methyl-2,6-dioxo-9-phenyl-3,5-dioxa-9,11- diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 362

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((1R,7S)- 11-methyl-2,6-dioxo-9-phenyl-3,5-dioxa-9,11- diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-2- oxoethyl)benzamide HL- 363

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((1R,7S)-11-methyl-2,6-dioxo-9-phenyl-3,5- dioxa-9,11-diaza-4- borabicyclo[5.3.1]undecan-4-yl)butyl)amino)-1- oxobutan-2-yl)-6- phenylpicolinamide HL- 364

N-((S)-1-(((R)-1-(4,8- dioxo-1,3,6,2- trioxaborocan-2-yl)-3-methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 365

(R)-2,5-dichloro-N-(2- ((1-(4,8-dioxo-1,3,6,2- trioxaborocan-2-yl)-3-methylbutyl)amino)-2- oxoethyl)benzamide HL- 366

N-((2S,3R)-1-(((R)-1- (4,8-dioxo-1,3,6,2- trioxaborocan-2-yl)-3-methylbutyl)amino)-3- hydroxy-1-oxobutan-2- yl)-6- phenylpicolinamideHL- 367

N-((S)-1-(((R)-3- methyl-1-((R)-5- methyl-4,8-dioxo-1,3,6,2-trioxaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 368

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((R)-5- methyl-4,8-dioxo-1,3,6,2-trioxaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 369

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((R)-5-methyl-4,8-dioxo-1,3,6,2- trioxaborocan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 370

N-((S)-1-(((R)-3- methyl-1-((R)-5- methyl-4,8-dioxo-1,3,6,2-trioxaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 371

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((R)-5- methyl-4,8-dioxo-1,3,6,2-trioxaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 372

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((R)-5-methyl-4,8-dioxo-1,3,6,2- trioxaborocan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 373

N-((S)-1-(((R)-1- ((5R,7S)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-trioxaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 374

2,5-dichloro-N-(2-(((R)- 1-((5R,7S)-5,7- dimethyl-4,8-dioxo-1,3,6,2-trioxaborocan-2- yl)-3- methylbutyl)amino)-2- oxoethyl)benzamideHL- 375

N-((2S,3R)-1-(((R)-1- ((5R,7S)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-trioxaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 376

N-((S)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-trioxaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 377

2,5-dichloro-N-(2-(((R)- 1-((5R,7R)-5,7- dimethyl-4,8-dioxo-1,3,6,2-trioxaborocan-2- yl)-3- methylbutyl)amino)-2- oxoethyl)benzamideHL- 378

N-((2S,3R)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-trioxaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 379

N-((S)-1-(((R)-1- ((5R,7S)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-trioxaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 380

2,5-dichloro-N-(2-(((R)- 1-((5R,7S)-5,7- dimethyl-4,8-dioxo-1,3,6,2-trioxaborocan-2- yl)-3- methylbutyl)amino)-2- oxoethyl)benzamideHL- 381

N-((2S,3R)-1-(((R)-1- ((5R,7S)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-trioxaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 382

N-((S)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-trioxaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 383

2,5-dichloro-N-(2-(((R)- 1-((5R,7R)-5,7- dimethyl-4,8-dioxo-1,3,6,2-trioxaborocan-2- yl)-3- methylbutyl)amino)-2- oxoethyl)benzamideHL- 384

N-((2S,3R)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-trioxaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 385

N-((S)-1-(((R)-1-(4,8- dioxo-1,3,6,2- dioxathiaborocan-2-yl)-3-methylbutyl)amino)- 1-oxo-3-phenylpropan- 2-yl)pyrazine-2- carboxamideHL- 386

(R)-2,5-dichloro-N-(2- ((1-(4,8-dioxo-1,3,6,2- dioxathiaborocan-2-yl)-3-methylbutyl)amino)- 2-oxoethyl)benzamide HL- 387

N-((2S,3R)-1-(((R)-1- (4,8-dioxo-1,3,6,2- dioxathiaborocan-2-yl)-3-methylbutyl)amino)- 3-hydroxy-1-oxobutan- 2-yl)-6- phenylpicolinamideHL- 388

N-((S)-1-(((R)-3- methyl-1-((R)-5- methyl-4,8-dioxo- 1,3,6,2-dioxathiaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 389

2,5-dichloro-N-((S)-1- (((R)-3-methyl-1-((R)- 5-methyl-4,8-dioxo-1,3,6,2- dioxathiaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)benzamide HL- 390

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((R)-5-methyl-4,8-dioxo-1,3,6,2- dioxathiaborocan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 391

N-((S)-1-(((R)-3- methyl-1-((R)-5- methyl-4,8-dioxo- 1,3,6,2-dioxathiaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 392

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((R)-5- methyl-4,8-dioxo- 1,3,6,2-dioxathiaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 393

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((R)-5-methyl-4,8-dioxo-1,3,6,2- dioxathiaborocan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 394

N-((S)-1-(((R)-1- ((5R,7S)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 1-oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 395

2,5-dichloro-N-(2-(((R)- 1-((5R,7S)-5,7- dimethyl-4,8-dioxo- 1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL-396

N-((2S,3R)-1-(((R)-1- ((5R,7S)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 397

N-((S)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 1-oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 398

2,5-dichloro-N-(2-(((R)- 1-((5R,7R)-5,7- dimethyl-4,8-dioxo- 1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL-399

N-((2S,3R)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 400

N-((S)-1-(((R)-1- ((5R,7S)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 1-oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 401

2,5-dichloro-N-(2-(((R)- 1-((5R,7S)-5,7- dimethyl-4,8-dioxo- 1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL-402

N-((2S,3R)-1-(((R)-1- ((5R,7S)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 403

N-((S)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 1-oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 404

2,5-dichloro-N-(2-(((R)- 1-((5R,7R)-5,7- dimethyl-4,8-dioxo- 1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL-405

N-((2S,3R)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4,8-dioxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 406

N-((S)-1-(((R)-3- methyl-1-(4-oxo- 1,3,6,2- dioxathiaborocan-2-yl)butyl)amino)-1-oxo- 3-phenylpropan-2- yl)pyrazine-2- carboxamide HL-407

(R)-2,5-dichloro-N-(2- ((3-methyl-1-(4-oxo- 1,3,6,2- dioxathiaborocan-2-yl)butyl)amino)-2- oxoethyl)benzamide HL- 408

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1-(4- oxo-1,3,6,2-dioxathiaborocan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 409

N-((S)-1-(((R)-3- methyl-1-((R)-7- methyl-4-oxo-1,3,6,2-dioxathiaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 410

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((R)-7- methyl-4-oxo-1,3,6,2-dioxathiaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 411

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((R)-7-methyl-4-oxo- 1,3,6,2-dioxathiaborocan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 412

N-((S)-1-(((R)-3- methyl-1-((R)-7- methyl-4-oxo-1,3,6,2-dioxathiaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 413

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((R)-5- methyl-4,8-dioxo- 1,3,6,2-dioxathiaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 414

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((R)-5-methyl-4,8-dioxo-1,3,6,2- dioxathiaborocan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenypicolinamide HL- 415

N-((S)-1-(((R)-1- ((5S,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 1-oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 416

2,5-dichloro-N-(2-(((R)- 1-((5S,7R)-5,7- dimethyl-4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL-417

N-((2S,3R)-1-(((R)-1- ((5S,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 418

N-((S)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 1-oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 419

2,5-dichloro-N-(2-(((R)- 1-((5R,7R)-5,7- dimethyl-4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL-420

N-((2S,3R)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 421

N-((S)-1-(((R)-1- ((5S,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 1-oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 422

2,5-dichloro-N-(2-(((R)- 1-((5S,7R)-5,7- dimethyl-4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL-423

N-((2S,3R)-1-(((R)-1- ((5S,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 424

N-((S)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 1-oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 425

2,5-dichloro-N-(2-(((R)- 1-((5R,7R)-5,7- dimethyl-4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL-426

N-((2S,3R)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxathiaborocan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 427

N-((S)-1-(((R)-3- methyl-1-(4-oxo- 1,3,6,2-dioxazaborocan-2-yl)butyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 428

(R)-2,5-dichloro-N-(2- ((3-methyl-1-(4-oxo- 1,3,6,2-dioxazaborocan-2-yl)butyl)amino)-2- oxoethyl)benzamide HL- 429

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1-(4- oxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 430

N-((S)-1-(((R)-3- methyl-1-((R)-7- methyl-4-oxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 431

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((R)-7- methyl-4-oxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 432

N-((2S,3R)-3)-hydroxy- 1-(((R)-3-methyl-1- ((R)-7-methyl-4-oxo-1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 433

N-((S)-1-(((R)-3- methyl-1-((R)-7- methyl-4-oxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 434

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((R)-5- methyl-4,8-dioxo-1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-2- oxoethyl)benzamide HL- 435

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((R)-5-methyl-4,8-dioxo-1,3,6,2- dioxazaborocan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 436

N-((S)-1-(((R)-1- ((5S,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 437

2,5-dichloro-N-(2-(((R)- 1-((5S,7R)-5,7- dimethyl-4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-2- oxoethyl)benzamide HL- 438

N-((2S,3R)-1-(((R)-1- ((5S,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 439

N-((S)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 440

2,5-dichloro-N-(2-(((R)- 1-((5R,7R)-5,7- dimethyl-4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-2- oxoethyl)benzamide HL- 441

N-((2S,3R)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 442

N-((S)-1-(((R)-1- ((5S,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 443

2,5-dichloro-N-(2-(((R)- 1-((5S,7R)-5,7- dimethyl-4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-2- oxoethyl)benzamide HL- 444

N-((2S,3R)-1-(((R)-1- ((5S,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 445

N-((S)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 446

2,5-dichloro-N-(2-(((R)- 1-((5R,7R)-5,7- dimethyl-4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-2- oxoethyl)benzamide HL- 447

N-((2S,3R)-1-(((R)-1- ((5R,7R)-5,7-dimethyl- 4-oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 448

N-((S)-1-(((R)-3- methyl-1-(6-methyl-4- oxo-1,3,6,2- dioxazaborocan-2-yl)butyl)amino)-1-oxo- 3-phenylpropan-2- yl)pyrazine-2- carboxamide HL-449

(R)-2,5-dichloro-N-(2- ((3-methyl-1-(6-methyl- 4-oxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 450

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1-(6- methyl-4-oxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 451

N-((S)-1-(((R)-1-((R)- 6,7-dimethyl-4-oxo- 1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2-carboxamide HL- 452

2,5-dichloro-N-(2-(((R)- 1-((R)-6,7-dimethyl-4- oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-2- oxoethyl)benzamide HL- 453

N-((2S,3R)-1-(((R)-1- ((R)-6,7-dimethyl-4- oxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 454

N-((S)-1-(((R)-1-((R)- 6,7-dimethyl-4-oxo- 1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2-carboxamide HL- 455

2,5-dichloro-N-(2-(((R)- 1-((R)-5,6-dimethyl- 4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-2- oxoethyl)benzamide HL- 456

N-((2S,3R)-1-(((R)-1- ((R)-5,6-dimethyl-4,8- dioxo-1,3,6,2-dioxazaborocan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 457

N-((S)-1-(((R)-3- methyl-1-((5S,7R)- 5,6,7-trimethyl-4-oxo-1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 458

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((5S,7R)- 5,6,7-trimethyl-4-oxo-1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-2- oxoethyl)benzamide HL- 459

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((5S,7R)-5,6,7-trimethyl-4-oxo-1,3,6,2- dioxazaborocan-2- yl)butyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 460

N-((S)-1-(((R)-3- methyl-1-((5R,7R)- 5,6,7-trimethyl-4-oxo-1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 461

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((5R,7R)- 5,6,7-trimethyl-4-oxo-1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-2- oxoethyl)benzamide HL- 462

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((5R,7R)-5,6,7-trimethyl-4-oxo-1,3,6,2- dioxazaborocan-2- yl)butyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 463

N-((S)-1-(((R)-3- methyl-1-((5S,7R)- 5,6,7-trimethyl-4-oxo-1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 464

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((5S,7R)- 5,6,7-trimethyl-4-oxo-1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-2- oxoethyl)benzamide HL- 465

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((5S,7R)-5,6,7-trimethyl-4-oxo-1,3,6,2- dioxazaborocan-2- yl)butyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 466

N-((S)-1-(((R)-3- methyl-1-((5R,7R)- 5,6,7-trimethyl-4-oxo-1,3,6,2-dioxazaborocan- 2-yl)butyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 467

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((5R,7R)- 5,6,7-trimethyl-4-oxo-1,3,6,2-dioxazaborocan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 468

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((5R,7R)-5,6,7-trimethyl-4-oxo-1,3,6,2- dioxazaborocan-2- yl)butyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 469

N-((S)-1-(((R)-3- methyl-1-((2R,3R)- 2,3,4-trimethyl-6-oxotetrahydro-2H- 414,814- [1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-8- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 470

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((2R,3R)- 2,3,4-trimethyl-6-oxotetrahydro-2H- 414,814- [1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-8- yl)butyl)amino)-2- oxoethyl)benzamide HL- 471

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((2R,3R)-2,3,4- trimethyl-6-oxotetrahydro-2H- 414,814- [1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-8- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 472

N-((S)-1-(((R)-3- methyl-1-((2R,3R,5S)- 2,3,4,5-tetramethyl-6-oxotetrahydro-2H- 414,814- [1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-8- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 473

2,5-dichloro-N-(2-(((R)- 3-methyl-1- ((2R,3R,5S)-2,3,4,5- tetramethyl-6-oxotetrahydro-2H- 414,814- [1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-8- yl)butyl)amino)-2- oxoethyl)benzamide HL- 474

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((2R,3R,5S)-2,3,4,5-tetramethyl-6- oxotetrahydro-2H- 414,814- [1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-8- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 475

N-((S)-1-(((R)-1- ((2S,3R,5R)-4-ethyl- 2,3,5-trimethyl-6-oxotetrahydro-2H- 414,814- [1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-8- yl)-3- methylbutyl)amino)-1-oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamide HL- 476

2,5-dichloro-N-((S)-1- (((R)-1-((2S,3R,5R)-4- ethyl-2,3,5-trimethyl-6-oxotetrahydro-2H- 414,814- [1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-8- yl)-3- methylbutyl)amino)-1-oxo-3-phenylpropan-2- yl)benzamide HL- 477

N-((S)-1-(((R)-1- ((2S,3R,5R)-4-ethyl- 2,3,5-trimethyl-6-oxotetrahydro-2H- 414,814- [1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-8- yl)-3- methylbutyl)amino)-1-oxo-3-phenylpropan-2- yl)-6- phenylpicolinamide HL- 478

N-((S)-1-(((R)-3- methyl-1-(6-methyl-4,9- dioxo-1,3,6,2-dioxazaboronan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 479

(R)-2,5-dichloro-N-(2- ((3-methyl-1-(6-methyl- 4,9-dioxo-1,3,6,2-dioxazaboronan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 480

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1-(6- methyl-4,9-dioxo-1,3,6,2-dioxazaboronan- 2-yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 481

N-((S)-1-(((R)-1-((R)- 5,6-dimethyl-4,9-dioxo- 1,3,6,2-dioxazaboronan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2-carboxamide HL- 482

2,5-dichloro-N-(2-(((R)- 1-((R)-5,6-dimethyl- 4,9-dioxo-1,3,6,2-dioxazaboronan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL- 483

N-((2S,3R)-1-(((R)-1- ((R)-5,6-dimethyl-4,9- 4,9-dioxo-1,3,6,2-dioxazaboronan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 484

N-((S)-1-(((R)-3- methyl-1-((5R,7S)- 5,6,7-trimethyl-4,9- dioxo-1,3,6,2-dioxazaboronan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 485

2,5-dichloro-N-(2-(((R)- 3-methyl-1-((5R,7S)- 5,6,7-trimethyl-4,9-dioxo-1,3,6,2- dioxazaboronan-2- yl)butyl)amino)-2- oxoethyl)benzamideHL- 486

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1- ((5R,7S)-5,6,7-trimethyl-4,9-dioxo- 1,3,6,2-dioxazaboronan- 2-yl)butyl)amino)-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 487

N-((S)-1-(((R)-1-((R)- 6,8-dimethyl-4,9-dioxo- 1,3,6,2-dioxazaboronan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2-carboxamide HL- 488

2,5-dichloro-N-(2-(((R)- 1-((R)-6,8-dimethyl- 4,9-dioxo-1,3,6,2-dioxazaboronan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL- 489

N-((2S,3R)-1-(((R)-1- ((R)-6,8-dimethyl-4,9- dioxo-1,3,6,2-dioxazaboronan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 490

N-((S)-1-(((R)-1-((S)- 6,7-dimethyl-4,9-dioxo- 1,3,6,2-dioxazaboronan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2-carboxamide HL- 491

2,5-dichloro-N-(2-(((R)- 1-((S)-6,7-dimethyl-4,9- dioxo-1,3,6,2-dioxazaboronan-2-yl)- 3-methylbutyl)amino)- 2-oxoethyl)benzamide HL- 492

N-((2S,3R)-1-(((R)-1- ((S)-6,7-dimethyl-4,9- dioxo-1,3,6,2-dioxazaboronan-2-yl)- 3-methylbutyl)amino)- 3-hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 493

N-((S)-1-(((R)-3- methyl-1-(7-methyl- 4,10-dioxo-1,3,7,2-dioxazaborecan-2- yl)butyl)amino)-1-oxo- 3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 494

(R)-2,5-dichloro-N-(2- ((3-methyl-1-(7-methyl- 4,10-dioxo-1,3,7,2-dioxazaborecan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 495

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1-(7- methyl-4,10-dioxo-1,3,7,2-dioxazaborecan- 2-yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 496

N-((S)-1-(((R)-1-((R)- 6,7-dimethyl-4,10- dioxo-1,3,7,2-dioxazaborecan-2-yl)-3- methylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)pyrazine-2- carboxamide HL- 497

2,5-dichloro-N-(2-(((R)- 1-((R)-6,7-dimethyl- 4,10-dioxo-1,3,7,2-dioxazaborecan-2-yl)-3- methylbutyl)amino)-2- oxoethyl)benzamide HL- 498

N-((2S,3R)-1-(((R)-1- ((R)-6,7-dimethyl-4,10- dioxo-1,3,7,2-dioxazaborecan-2-yl)-3- methylbutyl)amino)-3- hydroxy-1-oxobutan-2-yl)-6- phenylpicolinamide HL- 499

N-((S)-1-(((R)-3- methyl-1-(7-methyl-4- oxo-1,3,7,2- dioxazaborecan-2-yl)butyl)amino)-1-oxo- 3-phenylpropan-2- yl)pyrazine-2- carboxamide HL-500

(R)-2,5-dichloro-N-(2- ((3-methyl-1-(7-methyl- 4-oxo-1,3,7,2-dioxazaborecan-2- yl)butyl)amino)-2- oxoethyl)benzamide HL- 501

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1-(7- methyl-4-oxo-1,3,7,2-dioxazaborecan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 502

N-((S)-1-(((R)-3- methyl-1-(7-methyl- 1,3,7,2-dioxazaborecan-2-yl)butyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 503

(R)-2,5-dichloro-N-(2- ((3-methyl-1-(7-methyl- 1,3,7,2-dioxazaborecan-2-yl)butyl)amino)-2- oxoethyl)benzamide HL- 504

N-((2S,3R)-3-hydroxy- 1-(((R)-3-methyl-1-(7- methyl-1,3,7,2-dioxazaborecan-2- yl)butyl)amino)-1- oxobutan-2-yl)-6-phenylpicolinamide HL- 505

N-((S)-1-(((R)-1-(4- ethyltetrahydro-2H- 414,814-[1,3,2]oxazaborolo[2,3- b][1,3,2]oxazaborol-8- yl)-3-methylbutyl)amino)-1- oxo-3-phenylpropan-2- yl)pyrazine-2- carboxamideHL- 506

(R)-2,5-dichloro-N-(2- ((1-(4-ethyltetrahydro- 2H-414,814-[1,3,2]oxazaborolo[2,3- b][1,3,2]oxazaborol-8- yl)-3-methylbutyl)amino)-2- oxoethyl)benzamide HL- 507

N-((2S,3R)-1-(((R)-1- (4-ethyltetrahydro-2H- 414,814-[1,3,2]oxazaborolo[2,3- b][1,3,2]oxazaborol-8- yl)-3-methylbutyl)amino)-3- hydroxy-1-oxobutan-2- yl)-6- phenylpicolinamide

Stability Study

Compounds were tested for their stability, under three differentconditions (see Table 2), by the following procedures:

-   -   1. Room Temperature and Dry: compounds were left at the room        temperature (20° C.) under inert dry gas;    -   2. 30° C. and 65% Humidity: compounds sealed with double bags        were put into a stability chamber. Temperature was set at 30° C.        while the humidity was controlled at 65%.    -   3. 37° C. pH=7.4 solution: compounds were dissolved in PBS        solution and then the entire solution was submerged under a        37° C. water bath.

TABLE 2 Stability study of designed chiral specific boron derivatives.Room Temp 30° C./ 37° C. Compound Dry 65% Humidity H₂O/pH 7.4 HL01-0 −HL01-11 + + + HL01-15 + + + HL01-17 + − Decompose Instant Note: “+”meaning stable, “−” meaning quickly degradable, as determined byRP-HPLC.

Cell Viability Assay 1. Cell Line

The multiple myeloma cell line MM1.S was obtained from the ATCC. Cellswere cultured in standard RPMI-1640 media (Hyclone) supplemented with10% heat-inactivated fetal bovine serum (Gibco), 1%penicillin/streptomycin (Gibco) and grown in a humidified incubator with5% CO₂ at 37° C.

Eight thousand MM1.S cells per well were seeded in tissueculture-treated 96-well plate (Nunc) and incubated overnight.

2. Compound Treatment

Eighteen hours after seeding, MM1.S cells were treated with a series ofconcentrations of five different compounds (Bortezomib, HL01-01,HL01-11, HL01-15, HL01-17) or DMSO vehicle control for 72 hrs in ahumidified incubator with 5% CO₂. at 37° C. The concentrations of fivedifferent compounds were 0.3, 1, 3.16, 10, 31.6, 100, 316, and 1000 nM.Each well had the same DMSO concentration of 0.05%.

3. Cell Viability Assay (MTS Assay)

The effects of compounds on cell viability were assessed using CellTiter96®A Queous One solution Reagent (Promega; G3580).

After being treated with various compounds for 72 hrs, cells in the96-well plate were centrifuged 1000 rpm for 3 minutes, and 180 ulsupernatant were removed from each well. Cells were incubated with 20 ulCellTiter 96®A Queous One solution Reagent and put into incubator with5% CO₂. at 37° C. for an additional 4 hrs. The absorbance was measuredat 490 nm with Automatic Microplate reader (Infinite M 1000 pro, Tecan).There was a liner relationship (r²=0.99) between absorbance and cellnumber in each plate format. Four sets of experiments for each drugcombinations were carried out. Cell viability (Percentage of CellSurvival) was calculated by the following formula: cell viability(%)=(average absorbance of treated group-average absorbance ofblank)/(average absorbance of untreated group−average absorbance ofblank)×100%. IC50 values were calculated using Prism software.

Results

The cytotoxic effects of compounds including Bortezomib, HL01-11, andHL01-15 on MM1.S cell were assessed using the MTS assay. It was foundthat all compounds could dose-dependently decrease the cell viability inMM1.S cell. As represented by the cell line assay shown in FIG. 1.Bortezomib and HL01-11 exhibited strong cytotoxic effects on MM1.S cellsand both compounds had similar IC₅₀ values nearly 2 nM. The effect ofHL01-15 was weaker than the other compounds. The IC₅₀ value of HL01-15was 6.85 nM, as set forth in Table 3:

TABLE 3 Compound IC₅₀ (nM) Bortezomib 1.76 HL01-01 1.96 HL01-11 1.62HL01-15 6.85 HL01-17 (Ixazomib) 9.45

Five compounds exhibited cytotoxicity in MM1.S cells. MM1.S cells weretreated with various concentrations of Bortezomib, HL01-11, and HL01-15for 72 h. Cell viability was assessed using the MTS assay. Mean±SEM(n=4).

Although the disclosure has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous forms, thereof, wherein: Z₃ is a peptidecontaining 1-20 amide bonds and boron atom attaches to a C atom, not anN atom nor —C═O; Y₃ is C₁ to C₅, O, S, NH, or NR; R represents analiphatic or aromatic group with or without heteroatom or functionalgroup, such as COOH, OH, or NH₂; each Ra₁ and Ra₂ independently is H,aliphatic, or aromatic substitution group; each Ra₃ and Ra₄independently is H, aliphatic, or aromatic substitution group; q is 0,1, or 2; and r is 0, 1, or
 2. 2. The compound of claim 1, wherein Z₃ ischaracterized by the bare bones structure or its derivatives of theformula (XI-1):


3. The compound of claim 1, wherein Z₃ is characterized by the barebones structure or its derivatives of the formula (XI-2):


4. The compound of claim 1, wherein Z₃ is characterized by the barebones structure or its derivatives of the formula (XI-3):


5. The compound of claim 1, wherein said compound is one of:


6. A compound of the formula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof, wherein: Z₃ is a peptidecontaining 1-20 amide bonds and boron atom attaches to a C atom, not anN atom nor —C═O; each of Y₁, Y₂, and Y₃ independently is O, S, NH, orNR; Y₃ can also be C₁ to C₅; R represents an aliphatic or aromatic groupwith or without heteroatom or functional group, such as COOH, OH, orNH₂; each Rb₁ and Rb₂ independently is H, aliphatic, or aromaticsubstitution group; Rb₁ and Rb₂ can also be a double bond, such ascarbonyl group; each Rb₃ and Rb₄ independently is H, aliphatic, oraromatic substitution group; s is 0, 1, or 2; and t is 0, 1, or
 2. 7.The compound of claim 6, wherein said compound is characterized by theformula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof, wherein: Z₃ is a peptidecontaining 1-20 amide bonds and boron atom attaches to a C atom, not anN atom or —C═O; each Rc₁ and Rc₂ independently is H, aliphatic, oraromatic substitution group; each Rc₃ and Rc₄ independently is H,aliphatic, or aromatic substitution group, —(CH2)_(p)—COOH and—(CH2)_(p)—COOR wherein R is an aliphatic or aromatic group, with orwithout heteroatom or functional group, such as COOH, OH, or NH₂; and uis 0, 1, or
 2. 8. The compound of claim 6, wherein said compound ischaracterized by the formula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous forms, thereof, wherein: Z₃ is a peptidecontaining 1-20 amide bonds and boron atom attaches to a C atom, not anN atom or —C═O; and each Rd₁ and Rd₂ independently is H, aliphatic,aromatic substitution group, —(CH2)_(p)—COOH and —(CH2)_(p)—COOR whereinR is an aliphatic or aromatic group with or without heteroatom orfunctional group, such as COOH, OH, or NH₂.
 9. The compound of claim 6,wherein said compound is characterized by the formula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof, wherein: Z₃ is a peptidecontaining 1-20 amide bonds and boron atom attaches to a C atom, not anN atom nor —C═O; each Re₁ and Re₂ independently is H, aliphatic,aromatic substitution group, —(CH2)_(p)—COOH and —(CH2)_(p)—COOR whereinR is an aliphatic or aromatic group with or without heteroatom orfunctional group, such as COOH, OH, or NH₂; and each Re₃ and Re₄independently is H, aliphatic, aromatic substitution group,—(CH2)_(p)—COOH and —(CH2)_(p)—COOR wherein R is an aliphatic oraromatic group.
 10. The compound of claim 6, wherein said compound ischaracterized by the formula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof, wherein: Z₃ is a peptidecontaining 1-20 amide bonds and boron atom attaches to a C atom, not anN atom or —C═O; each Rf₁ and Rf₂ independently is H, aliphatic, aromaticsubstitution group; each Rf₃ and Rf₄ independently is H, aliphatic,aromatic substitution group, —(CH₂)_(p)—COOH and —(CH2)_(p)—COOR whereinR is an aliphatic or aromatic group with or without heteroatom orfunctional group, such as COOH, OH, or NH₂; and v is 0, 1, or
 2. 11. Thecompound of claim 6, wherein said compound is characterized by theformula:

or a pharmaceutically acceptable salt, solvate, and/or hydrate,polymorph crystal or amorphous form thereof, wherein: Z₃ is a peptidecontaining 1-20 amide bonds and boron atom attaches to a C atom, not anN atom nor —C═O; R represents an aliphatic or aromatic group with orwithout heteroatom or functional group, such as COOH, OH, or NH₂; eachRg₁ and Rg₂ independently is H, aliphatic, aromatic substitution group;each Rg₃ and Rg₄ independently is H, aliphatic, aromatic substitutiongroup, —(CH2)_(p)—COOH and —(CH2)_(p)—COOR wherein R is an aliphatic oraromatic group with or without heteroatom or functional group, such asCOOH, OH, NH₂; and w is 0, 1, or
 2. 12. The compound of claim 6, whereinsaid compound is one of:


13. A composition for treating cancer, a cancerous condition, oramyloidosis in a human or mammal, comprising as active ingredient apharmaceutically effective amount of a compound of claim 1 or apharmaceutically acceptable acid addition salt thereof, in combinationwith pharmaceutically acceptable carriers, diluents, or excipients. 14.The composition of claim 13 comprising active ingredient in an amounteffective to treat multiple myeloma or amyloidosis.
 15. A method oftreating cancer, a cancerous condition, or amyloidosis in a human ormammal host in need of such treatment, which comprises perorally,parentally, or rectally administering to said host an effective cancer,cancerous condition, or amyloidosis treatment amount of a compound ofclaim 1 or a pharmaceutically acceptable acid addition salt thereof. 16.A composition for treating cancer, a cancerous condition, or amyloidosisin a human or mammal, comprising as active ingredient a pharmaceuticallyeffective amount of a compound of claim 6 or a pharmaceuticallyacceptable acid addition salt thereof, in combination withpharmaceutically acceptable carriers, diluents, or excipients.
 17. Thecomposition of claim 16 comprising active ingredient in an amounteffective to treat multiple myeloma or amyloidosis.
 18. A method oftreating cancer, a cancerous condition, or amyloidosis in a human ormammal host in need of such treatment, which comprises perorally,parentally, or rectally administering to said host an effective canceror cancerous condition treatment amount of a compound of claim 6 or apharmaceutically acceptable acid addition salt thereof.